Devices, systems, and methods for myocardial infarct border zone reinforcement

ABSTRACT

Devices, systems, and methods for myocardial infarct border zone reinforcement. In at least one embodiment of a suction/infusion catheter for facilitating myocardial infarct border zone reinforcement, the catheter comprises one or more apertures defined along a portion of the catheter at or near a distal end of the catheter, a first configuration when the suction/infusion catheter is at least partially extended from a delivery catheter, and a second configuration when the at least one suction/infusion catheter is positioned within the delivery catheter, the second configuration different from the first configuration, wherein the suction/infusion catheter, when introduced into a pericardial space surrounding a heart at or near a myocardial infarct border zone, is operable to inject a glue-like substance through a lumen of the suction/infusion catheter and out from the one or more apertures to deliver the glue-like substance into the pericardial space at or near the myocardial infarct border zone.

PRIORITY

This U.S. continuation patent application is related to, and claims thepriority benefit of, U.S. Nonprovisional patent application Ser. No.12/596,970, filed Oct. 21, 2009, which is related to, claims thepriority benefit of, and is a U.S. national stage application of,International Patent Application No. PCT/US2008/060487, filed Apr. 16,2008, which (i) claims priority to International Patent Application No.PCT/US2008/053061, filed Feb. 5, 2008, International Patent ApplicationNo. PCT/US2008/015207, filed Jun. 29, 2007, and U.S. Provisional PatentApplication Ser. No. 60/914,452, filed Apr. 27, 2007, and (ii) isrelated to, claims the priority benefit of, and in at least somedesignated countries should be considered a continuation-in-partapplication of, International Patent Application No. PCT/US2008/056666,filed Mar. 12, 2008, which is related to, claims the priority benefit ofand in at least some designated countries should be considered acontinuation-in-part application of, International Patent ApplicationNo. PCT/US2008/053061, filed Feb. 5, 2008, which is related to, claimsthe priority benefit of, and in at least some designated countriesshould be considered a continuation-in-part application of,International Application Serial No. PCT/US2007/015207, filed Jun. 29,2007, which claims priority to U.S. Provisional Patent Application Ser.No. 60/914,452, filed Apr. 27, 2007, and U.S. Provisional PatentApplication Ser. No. 60/817,421, filed Jun. 30, 2006. The contents ofeach of these applications are hereby incorporated by reference in theirentirety into this disclosure.

BACKGROUND

Ischemic heart disease, or coronary heart disease, kills more Americansper year than any other single cause. In 2004, one in every five deathsin the United States resulted from ischemic heart disease. Indeed, thedisease has had a profound impact worldwide. If left untreated, ischemicheart disease can lead to chronic heart failure, which can be defined asa significant decrease in the heart's ability to pump blood. Chronicheart failure is often treated with drug therapy.

Ischemic heart disease is generally characterized by a diminished flowof blood to the myocardium and is also often treated using drug therapy.Although many of the available drugs may be administered systemically,local drug delivery (“LDD”) directly to the heart can result in higherlocal drug concentrations with fewer systemic side effects, therebyleading to improved therapeutic outcomes.

Cardiac drugs may be delivered locally via catheter passing through theblood vessels to the inside of the heart. However, endoluminal drugdelivery has several shortcomings, such as: (1) inconsistent delivery,(2) low efficiency of localization, and (3) relatively rapid washoutinto the circulation.

To overcome such shortcomings, drugs may be delivered directly into thepericardial space, which surrounds the external surface of the heart.The pericardial space is a cavity formed between the heart and therelatively stiff pericardial sac that encases the heart. Although thepericardial space is usually quite small because the pericardial sac andthe heart are in such close contact, a catheter may be used to inject adrug into the pericardial space for local administration to themyocardial and coronary tissues. Drug delivery methods that supply theagent to the heart via the pericardial space offer several advantagesover endoluminal delivery, including: (1) enhanced consistency and (2)prolonged exposure of the drug to the cardiac tissue.

In current practice, drugs are delivered into the pericardial spaceeither by the percutaneous transventricular method or by thetransthoracic approach. The percutaneous transventricular methodinvolves the controlled penetration of a catheter through theventricular myocardium to the pericardial space. The transthoracicapproach involves accessing the pericardial space from outside the heartusing a sheathed needle with a suction tip to grasp the pericardium,pulling it away from the myocardium to enlarge the pericardial space,and injecting the drug into the space with the needle.

For some patients with chronic heart failure, cardiac resynchronizationtherapy (“CRT”) can be used in addition to drug therapy to improve heartfunction. Such patients generally have an abnormality in conduction thatcauses the right and left ventricles to beat (i.e., begin systole) atslightly different times, which further decreases the heart'salready-limited function. CRT helps to correct this problem ofdyssynchrony by resynchronizing the ventricles, thereby leading toimproved heart function. The therapy involves the use of an implantabledevice that helps control the pacing of at least one of the ventriclesthrough the placement of electrical leads onto specified areas of theheart. Small electrical signals are then delivered to the heart throughthe leads, causing the right and left ventricles to beat simultaneously.

Like the local delivery of drugs to the heart, the placement of CRTleads on the heart can be challenging, particularly when the targetplacement site is the left ventricle. Leads can be placed using atransvenous approach through the coronary sinus, by surgical placementat the epicardium, or by using an endocardial approach. Problems withthese methods of lead placement can include placement at an improperlocation (including inadvertent placement at or near scar tissue, whichdoes not respond to the electrical signals), dissection or perforationof the coronary sinus or cardiac vein during placement, extendedfluoroscopic exposure (and the associated radiation risks) duringplacement, dislodgement of the lead after placement, and long andunpredictable times required for placement (ranging from about 30minutes to several hours).

Clinically, the only approved non-surgical means for accessing thepericardial space include the subxiphoid and the ultrasound-guidedapical and parasternal needle catheter techniques, and each methodsinvolves a transthoracic approach. In the subxiphoid method, a sheathedneedle with a suction tip is advanced from a subxiphoid position intothe mediastinum under fluoroscopic guidance. The catheter is positionedonto the anterior outer surface of the pericardial sac, and the suctiontip is used to grasp the pericardium and pull it away from the hearttissue, thereby creating additional clearance between the pericardialsac and the heart. The additional clearance tends to decrease thelikelihood that the myocardium will be inadvertently punctured when thepericardial sac is pierced.

Although this technique works well in the normal heart, there are majorlimitations in diseased or dilated hearts—the very hearts for which drugdelivery and CRT lead placement are most needed. When the heart isenlarged, the pericardial space is significantly smaller and the risk ofpuncturing the right ventricle or other cardiac structures is increased.Additionally, because the pericardium is a very stiff membrane, thesuction on the pericardium provides little deformation of thepericardium and, therefore, very little clearance of the pericardiumfrom the heart.

As referenced above, the heart is surrounded by a “sac” referred to asthe pericardium. The space between the surface of the heart and thepericardium can normally only accommodate a small amount of fluid beforethe development of cardiac tamponade, defined as an emergency conditionin which fluid accumulates in the pericardium. Therefore, it is notsurprising that cardiac perforation can quickly result in tamponade,which can be lethal. With a gradually accumulating effusion, however, asis often the case in a number of diseases, very large effusions can beaccommodated without tamponade. The key factor is that once the totalintrapericardial volume has caused the pericardium to reach thenoncompliant region of its pressure-volume relation, tamponade rapidlydevelops. Little W. C., Freeman G. L. (2006). “Pericardial Disease,”Circulation 113(12): 1622-1632.

Cardiac tamponade occurs when fluid accumulation in the intrapericardialspace is sufficient to raise the pressure surrounding the heart to thepoint where cardiac filling is affected. Ultimately, compression of theheart by a pressurized pericardial effusion results in markedly elevatedvenous pressures and impaired cardiac output producing shock which, ifuntreated, it can be rapidly fatal. Id.

The frequency of the different causes of pericardial effusion variesdepending in part upon geography and the patient population. Corey G. R.(2007). “Diagnosis and treatment of pericardial effusion.”http://patients.uptodate.com. A higher incidence of pericardial effusionis associated with certain diseases. For example, twenty-one percent ofcancer patients have metastases to the pericardium. The most common arelung (37% of malignant effusions), breast (22%), and leukemia/lymphoma(17%). Patients with HIV, with or without AIDS, are found to haveincreased prevalence, with 41-87% having asymptomatic effusion and 13%having moderate-to-severe effusion. Strimel W. J. e. a. (2006).“Pericardial Effusion,” http://www.emedicine.com/med/topic1786.htm.

End-stage renal disease is a major public health problem. In the UnitedStates, more than 350,000 patients are being treated with eitherhemodialysis or continuous ambulatory peritoneal dialysis. Venkat A.,Kaufmann K. R., Venkat K. (2006). “Care of the end-stage renal diseasepatient on dialysis in the ED.” Am J Emerg Med 24(7): 847-58. Renalfailure is a common cause of pericardial disease, producing largepericardial effusions in up to 20% of patients. Task Force members,Maisch B., Seferovic P. M., Ristic A. D., Erbel R., Rienmuller R., AdlerY., Tomkowski W. Z., Thiene G., Yacoub M. H., ESC Committee for PracticeGuidelines, Priori S. G., Alonso Garcia M. A., Blanc J.-J., Budaj A.,Cowie M., Dean V., Deckers J., Fernandez Burgos E., Lekakis J., LindahlB., Mazzotta G., Moraies J., Oto A., Smiseth O. A., Document Reviewers,Acar J., Arbustini E., Becker A. E., Chiaranda G., Hasin Y., Jenni R.,Klein W., Lang I., Luscher T, F., Pinto F. J., Shabetai R., Simoons M.L., Soler Soler J., Spodick D. H. (2004). “Guidelines on the Diagnosisand Management of Pericardial Diseases Executive Summary: The Task Forceon the Diagnosis and Management of Pericardial Diseases of the EuropeanSociety of Cardiology.” Eur Heart J 25(7): 587-610.

Viral pericarditis is the most common infection of the pericardium.Inflammatory abnormalities are due to direct viral attack, the immuneresponse (antiviral or anticardiac), or both. Id. Purulent (bacterial)pericarditis in adults is rare, but always fatal if untreated. Mortalityrate in treated patients is 40%, mostly due to cardiac tamponade,toxicity, and constriction. It is usually a complication of an infectionoriginating elsewhere in the body, arising by contiguous spread orhaematogenous dissemination. Id. Other forms of pericarditis includetuberculous and neoplastic.

The most common secondary malignant tumors are lung cancer, breastcancer, malignant melanoma, lymphomas, and leukemias. Effusions may besmall or large with an imminent tamponade. In almost two-thirds of thepatients with documented malignancy pericardial effusion is caused bynon-malignant diseases, e.g., radiation pericarditis, or opportunisticinfections. The analyses of pericardial fluid, pericardial or epicardialbiopsy are essential for the confirmation of malignant pericardialdisease. Id.

Management of pericardial effusions continues to be a challenge. Thereis no uniform consensus regarding the best way to treat this difficultclinical entity. Approximately half the patients with pericardialeffusions present with symptoms of cardiac tamponade. In these cases,symptoms are relieved by pericardial decompression, irrespective of theunderlying cause, Georghiou G. P., Stamler A., Sharoni E., Fichman-HornS., Berman M., Vidne B. A., Saute M. (2005). “Video-AssistedThoracoscopic Pericardial Window for Diagnosis and Management ofPericardial Effusions.” Ann Thorac Surg 80(2): 607-610. Symptomaticpericardiac effusions are common and may result from a variety ofcauses. When medical treatment has failed to control the effusion or adiagnosis is needed, surgical intervention is required, Id.

The most effective management of pericardial effusions has yet to beidentified. The conventional procedure is a surgically placedpericardial window under general anesthesia. This procedure portendssignificant operative and anesthetic risks because these patients oftenhave multiple comorbidities. Less invasive techniques such as blindneedle pericardiocentesis have high complication and recurrence rates.The technique of echocardiographic-guided pericardiocentesis withextended catheter drainage is performed under local anesthetic withintravenous sedation. Creating a pericardiostomy with a catheter inplace allows for extended drainage and sclerotherapy.Echocardiographic-guided pericardiocentesis has been shown to be a safeand successful procedure when performed at university-affiliated oracademic institutions. However, practices in community hospitals haverarely been studied in detail. Buchanan C. L., Sullivan V. V., LampmanR., Kulkarni M. G. (2003). “Pericardiocentesis with extended catheterdrainage: an effective therapy.” Ann Thorac Surg 76(3): 817-82.

The treatment of cardiac tamponade is drainage of the pericardialeffusion. Medical management is usually ineffective and should be usedonly while arrangements are made for pericardial drainage. Fluidresuscitation may be of transient benefit if the patient is volumedepleted (hypovolemic cardiac tamponade).

Surgical drainage (or pericardiectomy) is excessive for many patients.The best option is pericardiocentesis with the Seldinger technique,leaving a pigtail drainage catheter that should be kept in place untildrainage is complete. Sagrista Sauleda J., Permanyer Miralda G., SolerSoler J. (2005). “[Diagnosis and management of acute pericardialsyndromes].” Rev Esp Cardiol 58(7): 830-41. This less-invasive techniqueresulted in a short operative time and decreased supply, surgeon, andanesthetic costs. When comparing procedure costs of a pericardial windowversus an echo-guided pericardiocentesis with catheter drainage at ourinstitution, there was a cost savings of approximately $1,800/case infavor of catheter drainage. In an era of accelerating medical costs,these savings are of considerable importance. Buchanan C. L., SullivanV. V., Lampman R., Kulkarni M. G. (2003). “Pericardiocentesis withextended catheter drainage: an effective therapy.” Ann Thorac Surg76(3): 817-82.

Myocardial infarctions (heart attacks) affect a significant number ofpeople, typically resulting in damaged heart tissue from a lack of bloodflow. The area surrounding the myocardial infarct, known as the borderzone, is the border between the non-viable tissue from the myocardialinfarct and its surrounding viable tissue. Over time, as the border zoneexpands (due to a lack of myocardial infarct healing), the heart willfail, typically resulting in death.

Healthy myocardium is uniformly irrigated, meaning that the tissuereceives its needed blood flow in order to remain healthy. If suchtissue becomes deprived of blood (from a myocardial infarction), areasof the tissue may become “patchy” or contain “islands” of health tissueand/or damaged tissue.

Attempts to facilitate infarct healing date back to at least 1993, whenFleischmann et al. introduced a therapeutic method for open fractureswhich combined conventional negative pressure drainage with modernocclusive dressing. The technique later became known as vacuum-assistedclosure (VAC) technique, which obtained certification by the U.S. Foodand Drug Administration, Chen S. Z. et al. (2005), “Effects ofvacuum-assisted closure on wound microcirculation: an experimentalstudy.” Asian J. Surg. 28(3): 211-7. The VAC technique appliessub-atmospheric pressure by controlled suction through a porousdressing.

In 1999, Obdeijn and colleagues applied this new method for treatmentfor posteternotomy mediastinitis. Although scientific evidence for VACefficacy for promotion of wound healing is established, the effects onheart and lung function are still not fully understood. Petzina R. etal. (2007). “Hemodynamic effects of vacuum-assisted closure therapy incardiac surgery: assessment using magnetic resonance imaging.” J.Thorac. Cardiovasc. Surg. 133(5): 1154-62.

The major objectives of VAC are to clean the wound, reduce wound edemaand infection, improve local blood flow, and promote the growth ofhealthy granulation tissue. Chen et al. 2005. VAC has been shown tosignificantly increase blood volume, and the increase in blood flow wasrelated to the increase in capillary caliber, density, and angiogenesis.Id.

Negative pressure is thought to cause an increase in blood flow due to apressure gradient of blood between the wound and surrounding tissues.This would passively dilate the capillaries and open up the capillarybed of the organ of interest. The VAC treatment has also been shown torestore the integrity of the basement membrane and reduce theendothelial space.

The VAC device produces microdeformations of the wound surface incontact with a foam. An application of the microdeformational woundtherapy (MDWT) may cause local wound hypoxia, which is a potentstimulator of vascular endothelial growth factor (VEGF) production.Greene A. K. et al. (2006). “Microdeformational wound therapy: effectson angiogenesis and matrix metalloproteinases in chronic wounds of 3debilitated patients.” Ann. Plast. Surg. 56(4): 418-22. MDWT increasesangiogenesis and reduces metalloproteinase (MMP) activity, both of whichpromote chronic wound healing. Id.

For the left ventricle, it has been demonstrated that an imbalancebetween MMP and tissue inhibitor MMPs occurs in the post-myocardialinfarct (MI) myocardium, and that increased MMP proteolytic activityfacilitates post-MI remodeling and eventually LV dilation. Webb et al.,Circulation, September 2006; 114: 1020-1027.

Healing is an interdependent process that involves complex interactionsbetween cells, the cellular microenvironment, biochemical mediators, andextracellular matrix molecules that results in a functional restorationof the injured tissue. The rate of wound healing is restricted by theavailable vascular supply and the rates of formation of new capillariesand matrix molecules. Morykwas M. J. et al. (1997). “Vacuum-assistedclosure: a new method for wound control and treatment: animal studiesand basic foundation.” Ann. Plast. Surg. 38(6): 553-62. The increase inlocalized blood flow following application of sub-atmospheric pressuremay be due to active removal of the excess interstitial fluid from thetissues surrounding the wound, decompressing small blood vessels andrestoring blood flow. Id.

A mechanical stretch of adult cardiac myocytes or neonatal myocytescultured in serum-free media by 10 to 20 percent above resting lengthincreases protein synthesis without DNA synthesis (hypertrophy). Thisdemonstrates that cardiac myocytes can sense external load in theabsence of neuronal and hormonal factors. A stretch of cardiac myocytesin vitro also causes transcriptional activation of immediate-early genesfollowed by an induction of the fetal genes. VAC may provide the stretchstimulus known to show efficacy.

Previous studies on VAC therapy in pig models have shown that −125 mmHgis the optimal negative pressure for wound healing which has beenestablished as a standard pressure in clinical use. On the heartsurface, pressures as low as −25 mmHg have been shown to be effective inincreasing microvascular flow.

In continuous sub-atmospheric pressure-treated wound, the granulationtissue showed hyper-proliferative growth above the margins of the wound.In an intermittent sub-atmospheric pressure-treated wound, the meanincrease in rate of granulation tissue formation was significantlygreater than in control wounds. Morykwas M. J. et al., 1997.

A single mechanical stretch causes an up-regulation of cells whereasintermittent application of sub-atmospheric pressure results inrepetitive release of second messengers. This continual stimulation isshown in the more rapid deposition of granulation tissue in woundsexposed to intermittent sub-atmospheric pressure as compared to woundsexposed to continuous sub-atmospheric pressure. Changes in cellularshape increase proliferation and protein and matrix molecule synthesisand promote granulation tissue formation. Id.

Regarding heart reinforcement, left ventricular remodeling after acutemyocardial infarction is a complex process that either produces acompensated ventricle with stable hemodynamics or an uncompensatedventricle that progressively enlarges and eventually fails. Bowen F. W.et al. (2001). “Restraining acute infarct expansion decreasescollagenase activity in borderzone myocardium.” Ann. Thorac. Surg.72(6): 1950-6. The changes in the cardiac collagen network occur aftermyocardial infarct. Reparative fibrosis results in response to a loss ofmyocardial material after necrosis or apoptosis, due to myocardialischemia or senescence. Piuhola J. (2002). “Regulation of cardiacresponses to increased load: Role of endothelin-1, angiotensin II andcollagen XV.”

Materials currently available for cardiac patching include synthetics,such as woven nylon (Dacron) and expanded polytetrafluoroethlyene(ePTFE), as well as glutaraldehyde-cross-linked biological membranes,like bovine pericardium. Although such materials perform adequately tofill tissue voids or reinforce weaknesses, they have no capacity forbioresorption, and therefore do not become viable. Such patches becomeincorporated by fibrotic encapsulation and cannot restore regionaltissue functionality. Robinson K. A. et al. (2005). “Extracellularmatrix scaffold for cardiac repair.” Circulation 112 (9 Suppl): I135-43.

Polymer scaffolds can be produced from natural or synthetic materials.Natural materials may mimic the native cellular environment as they areoften extracellular matrix components, and may include collagen,hydroxyapatite, Matrigel, alginate, etc. Synthetic materials have theadvantage of having selected material properties such as strength,degradation time, porosity, and microstructure.

Growth factors can also be incorporated into the matrix, wherein definedshapes and sizes can be fabricated readily and reproducibly. Ideallysuch polymers must be biocompatible and bioabsorbable, nonimmunogenic,support cell growth, and be able to induce angiogenesis to supply thenewly formed tissue. The most widely used polymers in tissue engineeringfulfilling these criteria include the poly (alpha-hydroxy acids) of thealiphatic polyesters (polyglycolic acid (PGA), polylactic acid (PLA),and the copolymers (PLGA)) of these materials.

Bone marrow stromal cells (or mesenchymal stem cells) have been shown tohave the potential of differentiating into cardiomyocytes in vitro aftertreatment with 5-azacytidine. Because these cells can be harvestedrepeatedly by bone marrow aspiration, can be expanded significantly invitro, and do not require immunosuppression, they are an attractive cellsource for cellular cardiomyoplasty. Fuchs J. R. et al. (2001). “Tissueengineering: a 21st century solution to surgical reconstruction.” Ann.Thorac. Surg. 72(2): 577-91.

The second approach to myocardial tissue engineering involves seedingcells onto a biodegradable scaffold. Tissue-engineered constructs have adefinitive structure and may be more apt to produce a significantmyocardial augmentation when transplanted as opposed to a cellsuspension alone. Furthermore, biodegradable polymers such as PGA, andpoly-L-lactic acid are well suited for the delivery of a large number ofcells because of their high porosity and surface area, which also allowsfor the vascularization and structural integration of the new tissuewith surrounding native tissue after implantation. Fuchs, J. R. et al.,2001.

Clearly, there is a clinical need for a mini-invasive, safe andeffective approach to treatment of pericardial effusion and tamponade.The present application takes advantage of a safe and effectivepericardial access approach previously disclosed in combination with aspecial catheter used specifically for fluid drainage, fluid diagnosis,resuscitation and therapy delivery to treat the underlying cause of theeffusion.

Thus, there is need for an efficient, easy to use, and relativelyinexpensive device, system and technique that can be used to access theheart for local delivery of therapeutic and diagnostic substances, aswell as of CRT leads and other types of leads. There is also a need foran efficient, easy to use, and relatively inexpensive device, system andtechnique that can be used to access a space containing fluid within atissue to remove the fluid and to optionally deliver a substance ifnecessary. There is also a need for an efficient, easy to use, andrelatively inexpensive device, system and method that can be used toeffectively heal a myocardial infarct and reinforce its border zone.

BRIEF SUMMARY

Disclosed herein are devices, systems, and methods for myocardialinfarct healing and reinforcement of its border zone. According to atleast one embodiment of a device for myocardial infarct healing and/orborder zone reinforcement, the device comprises a suction/infusioncatheter with one or more apertures useful for delivering a substance toa target site within the pericardial space over the epicardial surfaceof the heart. In another embodiment, the suction/infusion cathetercomprises a “memory” as described herein.

According to at least one embodiment of a method of myocardial infarctborder zone reinforcement, the method comprises the steps of introducingat least one suction/infusion catheter having a lumen therethrough to apericardial space surrounding a heart at or near a myocardial infarctborder zone, the at least one suction/infusion catheter comprising oneor more apertures defined along a portion of the at least onesuction/infusion catheter at or near a distal end of the at least onesuction/infusion catheter, a first configuration when the at least onesuction/infusion catheter is at least partially extended from a deliverycatheter, and a second configuration when the at least onesuction/infusion catheter is positioned within the delivery catheter,the second configuration different from the first configuration,injecting a glue-like substance through the lumen of the at least onesuction/infusion catheter and out from the one or more apertures todeliver the glue-like substance into the pericardial space at or nearthe myocardial infarct border zone, and injecting magnetic cells throughthe lumen of the at least one suction/infusion catheter and out from theone or more apertures to deliver the magnetic cells into the pericardialspace at or near the myocardial infarct border zone, wherein themagnetic cells are attracted to the glue-like substance, and wherein themagnetic cells provide structural support to the myocardial infarctborder zone. In another embodiment, the glue-like substance comprises abiologic glue. In yet another embodiment, the biologic glue comprisesliposomes containing magnetic particles. In an additional embodiment,the liposomes comprise a peptide attached to an outer surface of theliposomes. In yet an additional embodiment, the peptide comprises anarginine-glycine-apsartate peptide.

According to at least one embodiment of a method of myocardial infarctborder zone reinforcement, the glue-like substance binds to a myocardialinfarct border zone. In another embodiment, the magnetic cells comprisebiologic cells. In yet another embodiment, the biologic cells comprisedermal fibroblasts. In an additional embodiment, the dermal fibroblastscontain magnetic particles. In yet an additional embodiment, themagnetic cells are attracted to a peptide attached to the glue-likesubstance.

According to at least one embodiment of a method of myocardial infarctborder zone reinforcement, the magnetic cells are magnetically attractedto the glue like substance. In another embodiment, the magnetic cells,when positioned within the pericardial space at or near the myocardialinfarct border zone, may reproduce to form a tissue, said tissueproviding structural support at the myocardial infarct border zone. Inyet another embodiment, the first configuration comprises a coiledconfiguration. In an additional embodiment, the coiled configurationcomprises a racquet shape. In yet an additional embodiment, the firstconfiguration comprises a coiled configuration, and the secondconfiguration comprises an uncoiled configuration.

According to at least one embodiment of a method of myocardial infarctborder zone reinforcement, the step of introducing the at least onesuction/infusion catheter is performed using a pericardial sac approach.In another embodiment, the step of introducing the at least onesuction/infusion catheter is performed by introducing the at least onesuction/infusion catheter into a jugular vein, through a superior venacava, and into the pericardial space. In yet another embodiment, thestep of introducing the at least one suction/infusion catheter isperformed by introducing the at least one suction/infusion catheter intoa femoral vein, through an inferior vena cava, and into the pericardialspace. In an additional embodiment, the myocardial infarct border zoneis at a left ventricle of the heart, and wherein the step of introducingthe at least one suction/infusion catheter comprises the introduction ofthe at least one suction/infusion catheter into the pericardial space ator near the left ventricle of the heart. In yet an additionalembodiment, the at least one suction/infusion catheter further comprisesa guide wire positioned at the distal end of the at least onesuction/infusion catheter, wherein the guide wire facilitatesintroduction of the at least one suction/infusion catheter in the stepof introducing the at least one suction/infusion catheter.

According to at least one embodiment of a method of myocardial infarctborder zone reinforcement, the at least one suction/infusion cathetercomprises two suction/infusion catheters. In another embodiment, the atleast one suction/infusion catheter comprises at least threesuction/infusion catheters. In yet another embodiment, the step ofextending the at least one suction/infusion catheter from the deliverycatheter allows for an increased surface area of at least onesuction/infusion catheter to be positioned at or near the myocardialinfarct border zone. In an additional embodiment, the method furthercomprises the step of introducing an occluder within the lumen of the atleast one suction/infusion catheter. In yet an additional embodiment,the occluder may partially or completely block one or more apertures ofthe at least one suction/infusion catheter.

According to at least one embodiment of a method of myocardial infarctborder zone reinforcement, the at least one suction/infusion catheterfurther comprises a support wire positioned along at least part of alength of the at least one suction/infusion catheter. In anotherembodiment, the support wire facilitates the step of introducing atleast one suction/catheter into the pericardial space. In yet anotherembodiment, the support wire is used to define the first configuration.In an additional embodiment, the support wire provides rigidity to theat least one suction/infusion catheter. In yet an additional embodiment,the method further comprises the step of introducing an occluder withinthe lumen of the at least one suction/infusion catheter, wherein thestep of introducing an occluder is facilitated by the support wire.

According to at least one embodiment of a suction/infusion catheter forfacilitating myocardial infarct border zone reinforcement, thesuction/infusion catheter comprises one or more apertures defined alonga portion of the suction/infusion catheter at or near a distal end ofthe suction/infusion catheter, a first configuration when thesuction/infusion catheter is at least partially extended from a deliverycatheter, and a second configuration when the suction/infusion catheteris positioned within the delivery catheter, the second configurationdifferent from the first configuration, wherein the suction/infusioncatheter, when introduced into a pericardial space surrounding a heartat or near a myocardial infarct border zone, is operable to inject aglue-like substance through a lumen of the suction/infusion catheter andout from the one or more apertures to deliver the glue-like substanceinto the pericardial space at or near the myocardial infarct borderzone. In another embodiment, the suction/infusion catheter is furtheroperable to inject magnetic cells through the lumen of thesuction/infusion catheter and out from the one or more apertures todeliver the magnetic cells into the pericardial space at or near themyocardial infarct border zone, wherein the magnetic cells are attractedto the glue-like substance, and wherein the magnetic cells providestructural support to the myocardial infarct border zone. In yet anotherembodiment, the first configuration comprises a coiled configuration. Inan additional embodiment, the coiled configuration comprises a racquetshape. In yet an additional embodiment, the first configurationcomprises a coiled configuration, and the second configuration comprisesan uncoiled configuration.

According to at least one embodiment of a suction/infusion catheter forfacilitating myocardial infarct border zone reinforcement, thesuction/infusion catheter further comprises a guide wire positioned atthe distal end of the suction/infusion catheter, wherein the guide wirefacilitates introduction of the suction/infusion catheter into thepericardial space. In another embodiment, the suction/infusion catheterfurther comprises an occluder positioned within a lumen of thesuction/infusion catheter. In yet another embodiment, the occluder maypartially or completely block one or more apertures of thesuction/infusion catheter. In an additional embodiment, thesuction/infusion catheter further comprises a support wire positionedalong at least part of a length of the suction/infusion catheter. In yetan additional embodiment, the support wire facilitates introduction ofthe suction/catheter into the pericardial space.

According to at least one embodiment of a suction/infusion catheter forfacilitating myocardial infarct border zone reinforcement, the supportwire is used to define the first configuration. In another embodiment,the support wire provides rigidity to the suction/infusion catheter. Inyet another embodiment, the glue-like substance comprises a biologicglue. In an additional embodiment, the biologic glue comprises liposomescontaining magnetic particles. In yet an additional embodiment, theliposomes comprise a peptide attached to an outer surface of theliposomes.

According to at least one embodiment of a suction/infusion catheter forfacilitating myocardial infarct border zone reinforcement, the peptidecomprises an arginine-glycine-apsartate peptide. In another embodiment,the glue-like substance binds to the myocardial infarct border zone. Inyet another embodiment, the magnetic cells comprise biologic cells. Inan additional embodiment, the biologic cells comprise dermalfibroblasts. In yet an additional embodiment, the dermal fibroblastscontain magnetic particles.

According to at least one embodiment of a suction/infusion catheter forfacilitating myocardial infarct border zone reinforcement, the magneticcells are attracted to a peptide attached to the glue-like substance. Inanother embodiment, the magnetic cells are magnetically attracted to theglue like substance. In yet another embodiment, the magnetic cells, whenpositioned within the pericardial space surrounding the heart at or nearthe myocardial infarct border zone, may reproduce to form a tissue, saidtissue providing structural support at the myocardial infarct borderzone.

According to at least one embodiment of a system for facilitatingmyocardial infarct border zone reinforcement, the system comprises anengagement catheter having a proximal end, a distal end, and a lumenpositioned therethrough, a delivery catheter having a proximal end, adistal end, and a lumen positioned therethrough, the delivery catheterpositioned at least partially within the lumen of the engagementcatheter, and at least one suction/infusion catheter positioned at leastpartially within the lumen of the delivery catheter, the at least onesuction/infusion catheter comprising one or more apertures defined alonga portion of the at least one suction/infusion catheter at or near adistal end of the at least one suction/infusion catheter, a firstconfiguration when the at least one suction/infusion catheter is atleast partially extended from a delivery catheter, and a secondconfiguration when the at least one suction/infusion catheter ispositioned within the delivery catheter, the second configurationdifferent from the first configuration, wherein the at least onesuction/infusion catheter, when introduced into a pericardial spacesurrounding a heart at or near a myocardial infarct border zone, isoperable to inject a glue-like substance through a lumen of the at leastone suction/infusion catheter and out from the one or more apertures todeliver the glue-like substance into the pericardial space at or nearthe myocardial infarct border zone. In another embodiment, the at leastone suction/infusion catheter is further operable to inject magneticcells through the lumen of the at least one suction/infusion catheterand out from the one or more apertures to deliver the magnetic cellsinto the pericardial space at or near the myocardial infarct borderzone, wherein the magnetic cells are attracted to the glue-likesubstance, and wherein the magnetic cells provide structural support tothe myocardial infarct border zone. In yet another embodiment, the firstconfiguration comprises a coiled configuration. In an additionalembodiment, the coiled configuration comprises a racquet shape. In yetan additional embodiment, the first configuration comprises a coiledconfiguration, and the second configuration comprises an uncoiledconfiguration.

According to at least one embodiment of a system for facilitatingmyocardial infarct border zone reinforcement, the at least onesuction/infusion catheter further comprises a guide wire positioned atthe distal end of the at least one suction/infusion catheter, whereinthe guide wire facilitates introduction of the at least onesuction/infusion catheter into the pericardial space. In anotherembodiment, the system further comprises an occluder positioned within alumen of the at least one suction/infusion catheter. In yet anotherembodiment, the occluder may partially or completely block one or moreapertures of the at least one suction/infusion catheter. In anadditional embodiment, the system further comprises a support wirepositioned along at least part of a length of the at least onesuction/infusion catheter. In yet an additional embodiment, the supportwire facilitates introduction of the at least one suction/catheter intothe pericardial space.

According to at least one embodiment of a system for facilitatingmyocardial infarct border zone reinforcement, the support wire is usedto define the first configuration. In another embodiment, the supportwire provides rigidity to the at least one suction/infusion catheter. Inyet another embodiment, the glue-like substance comprises a biologicglue. In an additional embodiment, the biologic glue comprises liposomescontaining magnetic particles. In yet an additional embodiment, theliposomes comprise a peptide attached to an outer surface of theliposomes.

According to at least one embodiment of a system for facilitatingmyocardial infarct border zone reinforcement, the peptide comprises anarginine-glycine-apsartate peptide. In another embodiment, the glue-likesubstance binds to the myocardial infarct border zone. In yet anotherembodiment, the magnetic cells comprise biologic cells. In an additionalembodiment, the biologic cells comprise dermal fibroblasts. In yet anadditional embodiment, the dermal fibroblasts contain magneticparticles.

According to at least one embodiment of a system for facilitatingmyocardial infarct border zone reinforcement, the magnetic cells areattracted to a peptide attached to the glue-like substance. In anotherembodiment, the magnetic cells are magnetically attracted to the gluelike substance. In yet another embodiment, the magnetic cells, whenpositioned within the pericardial space surrounding the heart at or nearthe myocardial infarct border zone, may reproduce to form a tissue, saidtissue providing structural support at the myocardial infarct borderzone.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A shows an embodiment of an engagement catheter and an embodimentof a delivery catheter as disclosed herein;

FIG. 1B shows a percutaneous intravascular pericardial delivery usinganother embodiment of an engagement catheter and another embodiment of adelivery catheter as disclosed herein;

FIG. 2A shows a percutaneous intravascular technique for accessing thepericardial space through a right atrial wall or atrial appendage usingthe engagement and delivery catheters shown in FIG. 1A;

FIG. 2B shows the embodiment of an engagement catheter shown in FIG. 2A;

FIG. 2C shows another view of the distal end of the engagement catheterembodiment shown in FIGS. 2A and 2B;

FIG. 3A shows removal of an embodiment of a catheter as disclosedherein;

FIG. 3B shows the resealing of a puncture according to an embodiment asdisclosed herein;

FIG. 4A to 4C show a closure of a hole in the atrial wall using anembodiment as disclosed herein;

FIG. 4D shows another closure of a hole in cardiac tissue using anotherembodiment as disclosed herein;

FIG. 4E shows yet another closure of a hole in cardiac tissue usinganother embodiment as disclosed herein;

FIG. 4F shows still another closure of a hole in cardiac tissue usinganother embodiment as disclosed herein;

FIG. 5A shows an embodiment of an engagement catheter as disclosedherein;

FIG. 5B shows a cross-sectional view of the proximal end of theengagement catheter shown in FIG. 5A;

FIG. 5C shows a cross-sectional view of the distal end of the engagementcatheter shown in FIG. 5A;

FIG. 5D shows the engagement catheter shown in FIG. 5A approaching aheart wall from inside of the heart;

FIG. 6A shows an embodiment of a delivery catheter as disclosed herein;

FIG. 6B shows a close-up view of the needle shown in FIG. 6A;

FIG. 6C shows a cross-sectional view of the needle shown in FIGS. 6A and6B;

FIG. 7 shows an embodiment of a delivery catheter as disclosed herein;

FIG. 8 shows an embodiment of a steering wire system within a steeringchannel;

FIG. 9A shows another embodiment of a steering wire system as disclosedherein, the embodiment being deflected in one location;

FIG. 9B shows the steering wire system shown in FIG. 9A, wherein thesteering wire system is deflected at two locations;

FIG. 9C shows the steering wire system shown in FIGS. 9A and 9B in itsoriginal position;

FIG. 10 shows a portion of another embodiment of a steering wire system;

FIG. 11 shows a cross-sectional view of another embodiment of a deliverycatheter as disclosed herein;

FIG. 12A shows an embodiment of a system for closing a hole in cardiactissue, as disclosed herein;

FIG. 12B shows another embodiment of a system for closing a hole incardiac tissue, as disclosed herein;

FIG. 12C shows another embodiment of a system for closing a hole incardiac tissue, as disclosed herein;

FIG. 13 shows another embodiment of a system for closing a hole incardiac tissue, as disclosed herein;

FIG. 14 shows another embodiment of a system for closing a hole incardiac tissue, as disclosed herein;

FIG. 15A shows another embodiment of a system for closing a hole incardiac tissue, as disclosed herein;

FIG. 15B shows the embodiment of FIG. 15A approaching cardiac tissue;

FIG. 15C shows the embodiment of FIGS. 15A-15C deployed on the cardiactissue;

FIG. 16A shows an embodiment of a portion of an apparatus for engaging atissue having a skirt positioned substantially within a sleeve, asdisclosed herein;

FIG. 16B shows another embodiment of a portion of an apparatus forengaging a tissue, as disclosed herein;

FIG. 16C shows an embodiment of a portion of an apparatus for engaging atissue having a skirt positioned substantially outside of a sleeve, asdisclosed herein;

FIG. 17A shows an embodiment of a portion of an apparatus for engaging atissue that has engaged a tissue, as disclosed herein;

FIG. 17B shows an embodiment of a portion of an apparatus for engaging atissue having an expanded skirt that has engaged a tissue, as disclosedherein;

FIG. 18A shows an embodiment of a portion of an apparatus for engaging atissue having a collapsed skirt present within a sleeve, as disclosedherein;

FIG. 18B shows an embodiment of a portion of an apparatus for engaging atissue having an expanded skirt, as disclosed herein;

FIG. 19 shows an embodiment of a system for engaging a tissue, asdisclosed herein;

FIG. 20A shows an embodiment of a portion of an apparatus for engaging atissue having a lead positioned therethrough, as disclosed herein;

FIG. 20B shows an embodiment of a portion of an apparatus for engaging atissue showing a needle, as disclosed herein;

FIG. 20C shows the embodiment of FIG. 20B having a lead positionedtherethrough;

FIG. 21A shows an embodiment of a portion of an apparatus for removingfluid from a tissue, as disclosed herein;

FIG. 21B shows an embodiment of a portion of an apparatus comprisinggrooves for removing fluid from a tissue, as disclosed herein;

FIG. 22 shows an embodiment of a portion of an apparatus for removingfluid from a tissue inserted within a heart, as disclosed herein;

FIG. 23A shows a side view of an embodiment of a catheter system asdisclosed herein;

FIG. 23B shows a side view of an embodiment of a catheter system asdisclosed herein having a partially extended suction/infusion catheter;

FIG. 24 shows an embodiment of a suction/infusion catheter as disclosedherein positioned within a heart;

FIG. 25A shows a side view of an embodiment of a multiplesuction/infusion catheter apparatus as disclosed herein;

FIG. 25B shows a side view of an embodiment of a multiplesuction/infusion catheter apparatus as disclosed herein with a partiallyextended suction/infusion catheter;

FIG. 25C shows a side view of an embodiment of a multiplesuction/infusion catheter apparatus as disclosed herein with twopartially extended suction/infusion catheters;

FIG. 26 shows an embodiment of a multiple suction/infusion catheterapparatus as disclosed herein positioned within a heart;

FIG. 27A shows a side view of an embodiment of a suction/infusioncatheter as disclosed herein having an occluder positioned partiallytherethrough;

FIG. 27B shows an end view of an embodiment of a suction/infusioncatheter as disclosed herein having an occluder positioned partiallytherethrough;

FIG. 28A shows an embodiment of a suction/infusion catheter as disclosedherein operable to deliver a glue-like substance to a target site; and

FIG. 28B shows an embodiment of a suction/infusion catheter as disclosedherein operable to deliver magnetic cells to a target site.

DETAILED DESCRIPTION

For the purposes of promoting an understanding of the principles of thepresent disclosure, reference will now be made to the embodimentsillustrated in the drawings, and specific language will be used todescribe the same. It will nevertheless be understood that no limitationof the scope of this disclosure is thereby intended.

The disclosed embodiments include devices, systems, and methods usefulfor accessing various tissues of the heart from inside the heart and forinfarct healing and reinforcement of a border zone. For example, variousembodiments provide for percutaneous, intravascular access into thepericardial space through an atrial wall or the wall of an atrialappendage. In at least some embodiments, the heart wall is aspirated andretracted from the pericardial sac to increase the pericardial spacebetween the heart and the sac and thereby facilitate access into thespace.

The disclosure of the present application also provides devices,systems, and methods to improve healing of tissue scar, including, butnot limited to, a myocardial infarct, and to mechanically reinforce theborder zone between viable and scar tissue to prevent dilation andfailure of organ (specifically heart failure). In at least oneembodiment, the devices, systems, and methods of the present disclosureare operable to utilize the VAC (vacuum-assisted closure) based on theprinciple of applying sub-atmospheric pressure by controlled suction tofacilitate the myocardial tissue healing after acute myocardialinfarction and its border zone in patients with severe compromised leftventricular function.

Unlike the relatively stiff pericardial sac, the atrial wall and atrialappendage are rather soft and deformable. Hence, suction of the atrialwall or atrial appendage can provide significantly more clearance of thecardiac structure from the pericardium as compared to suction of thepericardium. Furthermore, navigation from the intravascular region(inside of the heart) provides more certainty of position of vitalcardiac structures than does intrathoracic access (outside of theheart).

Access to the pericardial space may be used for identification ofdiagnostic markers in the pericardial fluid; for pericardiocentesis; andfor administration of therapeutic factors with angiogenic, myogenic, andantiarrhythmic potential. In addition, as explained in more detailbelow, epicardial pacing leads may be delivered via the pericardialspace, and an ablation catheter may be used on the epicardial tissuefrom the pericardial space.

In the embodiment of the catheter system shown in FIG. 1A, cathetersystem 10 includes an engagement catheter 20, a delivery catheter 30,and a needle 40. Although each of engagement catheter 20, deliverycatheter 30, and needle 40 has a proximal end and a distal end, FIG. 1Ashows only the distal end. Engagement catheter 20 has a lumen throughwhich delivery catheter 30 has been inserted, and delivery catheter 30has a lumen through which needle 40 has been inserted. Delivery catheter30 also has a number of openings 50 that can be used to transmit fluidfrom the lumen of the catheter to the heart tissue in close proximity tothe distal end of the catheter.

As shown in more detail in FIGS. 2A, 2B, 2C, engagement catheter 20includes a vacuum channel 60 used for suction of a targeted tissue 65 inthe heart and an injection channel 70 used for infusion of substances totargeted tissue 65, including, for example, a biological ornon-biological degradable adhesive. As is shown in FIGS. 2B and 2C,injection channel 70 is ring-shaped, which tends to provide relativelyeven dispersal of the infused substance over the targeted tissue, butother shapes of injection channels may be suitable. A syringe 80 isattached to injection channel 70 for delivery of the appropriatesubstances to injection channel 70, and a syringe 90 is attached tovacuum channel 60 through a vacuum port (not shown) at the proximal endof engagement catheter 20 to provide appropriate suction through vacuumchannel 60. At the distal end of engagement catheter 20, a suction port95 is attached to vacuum channel 60 for contacting targeted tissue 65,such that suction port 95 surrounds targeted tissue 65, which is therebyencompassed within the circumference of suction port 95. Althoughsyringe 90 is shown in FIG. 2B as the vacuum source providing suctionfor engagement catheter 20, other types of vacuum sources may be used,such as a controlled vacuum system providing specific suction pressures.Similarly, syringe 80 serves as the external fluid source in theembodiment shown in FIG. 2B, but other external fluid sources may beused.

A route of entry for use of various embodiments disclosed herein isthrough the jugular or femoral vein to the superior or inferior venacavae, respectively, to the right atrial wall or atrial appendage(percutaneously) to the pericardial sac (through puncture).

Referring now to FIG. 1B, an engagement catheter 100 is placed viastandard approach into the jugular or femoral vein. The catheter, whichmay be 4 or 5 Fr., is positioned under fluoroscopic or echocardiographicguidance into the right atrial appendage 110. Suction is initiated toaspirate a portion of atrial appendage 110 away from the pericardial sac120 that surrounds the heart. As explained herein, aspiration of theheart tissue is evidenced when no blood can be pulled back throughengagement catheter 100 and, if suction pressure is being measured, whenthe suction pressure gradually increases. A delivery catheter 130 isthen inserted through a lumen of engagement catheter 100. A smallperforation can be made in the aspirated atrial appendage 110 with aneedle such as needle 40, as shown in FIGS. 1A and 2A. A guide wire (notshown) can then be advanced through delivery catheter 130 into thepericardial space to secure the point of entry 125 through the atrialappendage and guide further insertion of delivery catheter 130 oranother catheter. Flouroscopy or echocardiogram can be used to confirmthe position of the catheter in the pericardial space. Alternatively, apressure tip needle can sense the pressure and measure the pressurechange from the atrium (about 10 mmHg) to the pericardial space (about 2mmHg). This is particularly helpful for transeptal access where punctureof arterial structures (e.g., the aorta) can be diagnosed and sealedwith an adhesive, as described in more detail below.

Although aspiration of the atrial wall or the atrial appendage retractsthe wall or appendage from the pericardial sac to create additionalpericardial space, CO2 gas can be delivered through a catheter, such asdelivery catheter 130, into the pericardial space to create additionalspace between the pericardial sac and the heart surface.

Referring now to FIG. 3A, the catheter system shown in FIG. 1B isretrieved by pull back through the route of entry. However, the punctureof the targeted tissue in the heart (e.g., the right atrial appendage asshown in FIG. 3A) may be sealed upon withdrawal of the catheter, whichprevents bleeding into the pericardial space. The retrieval of thecatheter may be combined with a sealing of the tissue in one of severalways: (1) release of a tissue adhesive or polymer 75 via injectionchannel 70 to seal off the puncture hole, as shown in FIG. 3B; (2)release of an inner clip or mechanical stitch to close off the hole fromthe inside of the cavity or the heart, as discussed herein; or (3)mechanical closure of the heart with a sandwich type mechanical devicethat approaches the hole from both sides of the wall (see FIGS. 4A, 4B,and 4C). In other words, closure may be accomplished by using, forexample, a biodegradable adhesive material (e.g., fibrin glue orcyanomethacrylate), a magnetic system, or an umbrella-shaped nitinolstent. An example of the closure of a hole in the atrium is shown inFIG. 3B. Engagement catheter 20 is attached to targeted tissue 95 usingsuction through suction port 60, Tissue adhesive 75 is injected throughinjection channel 70 to coat and seal the puncture wound in targetedtissue 95. Engagement catheter 20 is then withdrawn, leaving a plug oftissue adhesive 75 attached to the atrial wall or atrial appendage.

Other examples for sealing the puncture wound in the atrial wall orappendage are shown in FIGS. 4A-4F. Referring now to FIGS. 4A-4C, asandwich-type closure member, having an external cover 610 and aninternal cover 620, is inserted through the lumen of engagement catheter600, which is attached to the targeted tissue of an atrial wall 630.Each of external and internal covers 610 and 620 is similar to anumbrella in that it can be inserted through a catheter in its foldedconfiguration and expanded to an expanded configuration once it isoutside of the catheter. As shown in FIG. 4A, external cover 610 isdeployed (in its expanded configuration) on the outside of the atrialwall to seal a puncture wound in the targeted tissue, having alreadybeen delivered through the puncture wound into the pericardial space.Internal cover 620 is delivered through engagement catheter 600 (in itsfolded configuration), as shown in FIGS. 4A and 4B, by an elongateddelivery wire 615, to which internal cover 620 is reversibly attached(for example, by a screw-like mechanism). Once internal cover 620 is inposition on the inside of atrial wall 630 at the targeted tissue,internal cover 620 is deployed to help seal the puncture wound in thetargeted tissue (see FIG. 4C).

Internal cover 620 and external cover 610 may be made from a number ofmaterials, including a shape-memory alloy such as nitinol. Suchembodiments are capable of existing in a catheter in a foldedconfiguration and then expanding to an expanded configuration whendeployed into the body. Such a change in configuration can result from achange in temperature, for example. Other embodiments of internal andexternal covers may be made from other biocompatible materials anddeployed mechanically.

After internal cover 620 is deployed, engagement catheter 600 releasesits grip on the targeted tissue and is withdrawn, leaving thesandwich-type closure to seal the puncture wound, as shown in FIG. 4C.External cover 610 and internal cover 620 may be held in place using abiocompatible adhesive. Similarly, external cover 610 and internal cover620 may be held in place using magnetic forces, such as, for example, bythe inside face (not shown) of external cover 610 comprising a magnet,by the inside face (not shown) of internal cover 620 comprising amagnet, or both inside faces of external cover 610 or internal cover 620comprising magnets.

In the embodiment shown in FIGS. 4A, 4B, and 4C, the closure membercomprises external cover 610 and internal cover 620. However, in atleast certain other embodiments, the closure member need not have twocovers. For example, as shown in FIG. 4D, closure member 632 is made ofonly one cover 634. Cover 634 has a first face 636 and a second face638, and first face 636 is configured for reversible attachment todistal end 642 of delivery wire 640. Closure member 632 may be made ofany suitable material, including nitinol, which is capable oftransitioning from a folded configuration to an expanded configuration.

In the embodiment shown in FIG. 4E, a closure member 1500 comprises anexternal cover 1510 and an internal cover 1520 within a deliverycatheter 1530. External cover 1510 and internal cover 1520 are attachedat a joint 1540, which may be formed, for example, by a mechanicalattachment or by a magnetic attachment. In embodiments having a magneticattachment, each of the external cover and the internal cover may have aferromagnetic component that is capable of magnetically engaging theother ferromagnetic component.

Delivery catheter 1530 is shown after insertion through hole 1555 ofatrial wall 1550. Closure member 1500 may be advanced through deliverycatheter 1530 to approach atrial wall 1550 by pushing rod 1560. Rod 1560may be reversibly attached to internal cover 1520 so that rod 1560 maybe disconnected from internal cover 1520 after closure member 1500 isproperly deployed. For example, rod 1560 may engage internal cover 1520with a screw-like tip such that rod 1560 may be easily unscrewed fromclosure member 1500 after deployment is complete. Alternatively, rod1560 may simply engage internal cover 1520 such that internal cover 1520may be pushed along the inside of delivery catheter 1530 withoutattachment between internal cover 1520 and rod 1560.

Closure member 1500 is advanced through delivery catheter 1530 untilexternal cover 1510 reaches a portion of delivery catheter 1530 adjacentto atrial wall 1550; external cover 1510 is then pushed slowly out ofdelivery catheter 1530 into the pericardial space. External cover 1510then expands and is positioned on the outer surface of atrial wall 1550.When external cover 1510 is properly positioned on atrial wall 1550,joint 1540 is approximately even with atrial wall 1550 within hole 1555,Delivery catheter 1530 is then withdrawn slowly, causing hole 1555 toclose slightly around joint 1540. As delivery catheter 1530 continues tobe withdrawn, internal cover 1520 deploys from delivery catheter 1530,thereby opening into its expanded formation. Consequently, atrial wall1550 is pinched between internal cover 1520 and external cover 1510, andhole 1555 is closed to prevent leakage of blood from the heart.

FIG. 4F shows the occlusion of a hole (not shown) in atrial wall 1600due to the sandwiching of atrial wall 1600 between an external cover1610 and an internal cover 1620. External cover 1610 is shown deployedon the outside surface of atrial wall 1600, while internal cover 1620 isdeployed on the inside surface of atrial wall 1600. As shown, rod 1640is engaged with internal cover 1620, and delivery catheter 1630 is inthe process of being withdrawn, which allows internal cover 1620 tofully deploy. Rod 1640 is then withdrawn through delivery catheter 1630.An engagement catheter (not shown) may surround delivery catheter 1650,as explained more fully herein.

Other examples for sealing a puncture wound in the cardiac tissue areshown in FIGS. 12-15. Referring now to FIG. 12A, there is shown a plug650 having a first end 652, a second end 654, and a hole 656 extendingfrom first end 652 to second end 654. Plug 650 may be made from anysuitable material, including casein, polyurethane, silicone, andpolytetrafluoroethylene. Wire 660 has been slidably inserted into hole656 of plug 650. Wire 660 may be, for example, a guide wire or a pacinglead, so long as it extends through the hole in the cardiac tissue (notshown). As shown in FIG. 12A, first end 652 is covered with a radiopaquematerial, such as barium sulfate, and is therefore radiopaque. Thisenables the clinician to view the placement of the plug in the bodyusing radiographic imaging. For example, the clinician can confirm thelocation of the plug during the procedure, enabling a safer and moreeffective procedure for the patient.

As shown in FIG. 12A, first end 652 of plug 650 has a smaller diameterthan second end 654 of plug 650. Indeed, plug 680 shown FIG. 12B andplug 684 shown in FIGS. 13 and 14 have first ends that are smaller indiameter than their respective second ends. However, not all embodimentsof plug have a first end that is smaller in diameter than the secondend. For example, plug 682 shown in FIG. 12C has a first end with adiameter that is not smaller than the diameter of the second end. Bothtypes of plug can be used to close holes in cardiac tissue.

Referring again to FIG. 12A, elongated shaft 670 has a proximal end (notshown), a distal end 672, and a lumen 674 extending from the proximalend to distal end 672. Although no catheter is shown in FIG. 12A, plug650, wire 660, and shaft 670 are configured for insertion into a lumenof a catheter (see FIG. 14), such as an embodiment of an engagementcatheter disclosed herein. Plug 650 and shaft 670 are also configured tobe inserted over wire 660 and can slide along wire 660 because each oflumen 656 of plug 650 and lumen 674 of shaft 670 is slightly larger incircumference than wire 660.

As shown in FIGS. 13 and 14, shaft 672 is used to push plug 684 alongwire 674 within elongated tube 676 to and into the hole in the targetedcardiac tissue 678. Distal end 677 of elongated tube 676 is shownattached to cardiac tissue 678, but distal end 677 need not be attachedto cardiac tissue 678 so long as distal end 677 is adjacent to cardiactissue 678. Once plug 684 is inserted into the hole, wire 674 may bewithdrawn from the hole in plug 684 and the interior of the heart (notshown) and shaft 672 is withdrawn from elongated tube 676. In someembodiments, the plug is self-sealing, meaning that the hole of the plugcloses after the wire is withdrawn. For example, the plug may be madefrom a dehydrated protein matrix, such as casein or ameroid, whichswells after soaking up fluid. After shaft 672 is withdrawn, elongatedtube 676 can be withdrawn from the heart.

It should be noted that, in some embodiments, the wire is not withdrawnfrom the hole of the plug. For example, where the wire is a pacing lead,the wire may be left within the plug so that it operatively connects tothe CRT device.

Referring now to FIG. 12B, there is shown a plug 680 that is similar toplug 684. However, plug 680 comprises external surface 681 having aridge 683 that surrounds plug 680 in a helical or screw-like shape.Ridge 683 helps to anchor plug 680 into the hole of the targeted tissue(not shown). Other embodiments of plug may include an external surfacehaving a multiplicity of ridges surrounding the plug, for example, in acircular fashion.

FIGS. 15A-15C show yet another embodiment of a closure member forclosing a hole in a tissue. Spider clip 1700 is shown within catheter1702 and comprises a head 1705 and a plurality of arms 1710, 1720, 1730,and 1740. Each of arms 1710, 1720, 1730, and 1740 is attached at itsproximal end to head 1705. Although spider clip 1700 has four arms,other embodiments of spider clip include fewer than, or more than, fourarms. For example, some embodiments of spider clip have three arms,while others have five or more arms.

Referring again to FIGS. 15A-15C, arms 1710, 1720, 1730, and 1740 may bemade from any flexible biocompatible metal that can transition betweentwo shapes, such as a shape-memory alloy (e.g., nitinol) or stainlesssteel. Spider clip 1700 is capable of transitioning between an openposition (see FIG. 15A), in which the distal ends of its arms 1710,1720, 1730, and 1740 are spaced apart, and a closed position (see FIG.15C), in which the distal ends of arms 1710, 1720, 1730, and 1740 aregathered together. For embodiments made from a shape-memory alloy, theclip can be configured to transition from the open position to theclosed position when the metal is warmed to approximately bodytemperature, such as when the clip is placed into the cardiac tissue.For embodiments made from other types of metal, such as stainless steel,the clip is configured in its closed position, but may be transitionedinto an open position when pressure is exerted on the head of the clip.Such pressure causes the arms to bulge outward, thereby causing thedistal ends of the arms to separate.

In this way, spider clip 1700 may be used to seal a wound or hole in atissue, such as a hole through the atrial wall. For example, FIG. 15Bshows spider clip 1700 engaged by rod 1750 within engagement catheter1760. As shown, engagement catheter 1760 has a bell-shaped suction port1765, which, as disclosed herein, has aspirated cardiac tissue 1770.Cardiac tissue 1770 includes a hole 1775 therethrough, and suction port1765 fits over hole 1775 so as to expose hole 1775 to spider clip 1700.

Rod 1750 pushes spider clip 1700 through engagement catheter 1760 toadvance spider clip 1700 toward cardiac tissue 1770. Rod 1750 simplyengages head 1705 by pushing against it, but in other embodiments, therod may be reversibly attached to the head using a screw-type system. Insuch embodiments, the rod may be attached and detached from the headsimply by screwing the rod into, or unscrewing the rod out of, the head,respectively.

In at least some embodiments, the spider clip is held in its openposition during advancement through the engagement catheter by thepressure exerted on the head of the clip by the rod. This pressure maybe opposed by the biasing of the legs against the engagement catheterduring advancement.

Referring to FIG. 15C, spider clip 1700 approaches cardiac tissue 1770and eventually engages cardiac tissue 1770 such that the distal end ofeach of arms 1710, 1720, 1730, and 1740 contacts cardiac tissue 1770.Rod 1750 is disengaged from spider clip 1700, and spider clip 1700transitions to its closed position, thereby drawing the distal ends ofarms 1710, 1720, 1730, and 1740 together. As the distal ends of the armsare drawn together, the distal ends grip portions of cardiac tissue1770, thereby collapsing the tissue between arms 1710, 1720, 1730, and1740 such that hole 1775 is effectively closed.

Rod 1750 is then withdrawn, and engagement catheter 1760 is disengagedfrom cardiac tissue 1770. The constriction of cardiac tissue 1770 holdshole 1775 closed so that blood does not leak through hole 1775 afterengagement catheter 1760 is removed. After a relatively short time, thebody's natural healing processes permanently close hole 1775. Spiderclip 1700 may remain in the body indefinitely.

FIGS. 16A, 16B, and 16C show an embodiment of a portion of an apparatusfor engaging a tissue as disclosed herein. As shown in FIG. 16A, asleeve 1800 is present around at least a portion of an engagementcatheter 1810. Sleeve 1800, as described herein, may comprise a rigid orflexible tube having a lumen therethrough, appearing around the outsideof engagement catheter 1810 and slidingly engaging engagement catheter1810. In at least the embodiment shown in FIG. 16A, the distal end 1820of engagement catheter 1810 comprises a skirt 1830, shown in FIG. 16A asbeing housed within sleeve 1800. A delivery catheter 1840 may be presentwithin engagement catheter 1810 as shown to facilitate the delivery of aproduct (gas, liquid, and/or particulate(s)) to a target site. In thisembodiment, delivery catheter 1840 is present at least partially withinthe lumen of engagement catheter 1810, and engagement catheter is placedat least partially within the lumen of sleeve 1800.

Referring now to FIG. 16B, an embodiment of an apparatus as shown inFIG. 16A or similar to the embodiment shown in FIG. 16A is shown withsleeve 1800 being “pulled back” from the distal end of engagementcatheter 1810. As shown in FIG. 16B, as sleeve 1800 is pulled back (inthe direction of the arrow), skirt 1830 becomes exposed, and as sleeve1800 is no longer present around skirt 1830, skirt 1830 may optionallyexpand into a frusto-conical (“bell-shaped”) skirt 1830. Skirt 1830 maybe reversibly deformed (collapsed) when present within the lumen ofsleeve 1800 as shown in FIG. 16A and in FIG. 18A described in furtherdetail herein. It can be appreciated that many alternativeconfigurations of skirt 1830 to the frusto-conical configuration mayexist, including an irregular frusto-conical configuration, noting thata configuration of skirt 1830 having a distal portion (closest to atissue to be engaged) larger than a proximal position may benefit fromsuction of a larger surface area of a tissue as described in furtherdetail herein.

FIG. 16C shows an embodiment of an apparatus described herein having anexpanded skirt 1830. As shown in FIG. 16C, sleeve 1800 has been pulledback (in the direction of the arrow) so that the expanded configurationof skirt 1830 may be present to engage a tissue (not shown).

FIGS. 17A and 17B shown alternative embodiments of a portion of anapparatus for engaging a tissue as described herein. FIGS. 17A and 17Beach show a sleeve 1800, an engagement catheter 1810 having a skirt1830, and a delivery catheter 1840. In each figure, skirt 1830 is shownengaging a surface of a tissue 1850. In the embodiments shown in FIGS.17A and 17B, the relative sizes of the sleeves 1800, engagementcatheters 1810, and delivery catheters 1840 are similar as shown, butthe relative sizes of the skirts 1830 of the engagement catheters 1810are clearly different. The exemplary embodiment of the portion of anapparatus for engaging a tissue shown in FIG. 17A comprises a skirt 1830of the same or substantially similar relative size as the engagementcatheter 1810, meaning that the diameters of the engagement catheter1810 and the skirt 1830 shown in FIG. 17A are approximately the same.Conversely, the exemplary embodiment of the portion of an apparatus forengaging a tissue shown in FIG. 17B comprises a skirt 1830 notablylarger than the engagement catheter 1810, meaning that the diameters ofthe engagement catheter 1810 and the skirt 1830 at its widest pointshown in FIG. 17B are notably different. As shown in FIG. 17B, as skirt1830 extends from engagement catheter 1810 to tissue 1850, the diameterof skirt 1830 increases. As such, skirt 1830 of the embodiment shown inFIG. 17B may engage a larger surface area of a tissue (shown by 1860)than the embodiment of the skirt 1830 shown in FIG. 17A. The ability toengage a larger surface area of a tissue 1850 by skirt 1830 allows abetter reversible engagement of a tissue 1850 when a vacuum is providedas described in detail herein. This improved suction allows a personusing such an apparatus to more effectively engage a tissue 1850 thanwould otherwise be possible when skirt 1830 engages a smaller surfacearea of a tissue.

FIGS. 18A and 18B show perspective views of an embodiment of a portionof an apparatus for engaging a tissue. FIG. 18A represents an embodimentwhereby a skirt 1830 of an engagement catheter 1810 is positionedsubstantially within a sleeve 1800. FIG. 18B represents an embodimentwhereby a skirt 1830 of an engagement catheter 1810 is positionedoutside of s 1800. As such, the positioning of skirt 1830 within sleeve1800 can be seen in the embodiments of FIGS. 16A and 18A, and thepositioning of skirt 1830 outside of sleeve 1800 can be seen in theembodiments of FIGS. 16C and 18B.

As shown in FIG. 18A, skirt 1830 of engagement catheter 1810 ispositioned within sleeve 1800, whereby the configuration of skirt 1830is collapsed so that skirt 1830 may fit within sleeve 1800. As sleeve1800 moves in the direction of the arrow shown in FIG. 18B, skirt 1830becomes exposed and its configuration is allowed to expand because thereare no constraints provided by the inner wall of sleeve 1800.

The embodiments shown in FIGS. 18A and 18B also show an exemplaryembodiment of a configuration of an engagement catheter 1810. As shownin FIG. 18B, engagement catheter 1810 defines a number of apertures(representing lumens) present at the distal end of engagement catheter1810 (at the proximal end of skirt 1830), including, but not limited to,one or more vacuum ports 1870 (representing the aperture at or near thedistal end of a vacuum tube), and a delivery port 1880 (representing theaperture at or near the distal end of a delivery tube). A vacuum source(not shown) may be coupled to a suction port located at a proximal endof one or more vacuum tubes as described herein, whereby gas, fluid,and/or particulate(s) may be introduced into one or more vacuum ports1870 by the introduction of a vacuum at a vacuum port. Gas, fluid,and/or particulate(s) may be introduced from delivery aperture 1880 to atissue (not shown in FIG. 18A or 18B).

As shown by the exemplary embodiments of FIGS. 17A and 17B, the abilityfor a user of such an apparatus for engaging a tissue to obtain propersuction depends at least in part on the relative placement of skirt 1830and delivery catheter 1840 at or near a tissue 1850. As described indetail herein regarding the exemplary embodiment shown in FIG. 5D, if avacuum source provides suction through one or more vacuum ports 1870(shown in FIGS. 18A and 18B), but skirt 1830 has not effectively engageda tissue 1850, gas, fluid, and/or particulate(s) in the area of tissue1850 and/or gas, fluid and/or particulate(s) delivered via deliverycatheter 1840 to the area of tissue 1850 may be aspirated by one or morevacuum ports 1870. In a situation where skirt 1830 has effectivelyengaged a tissue 1850 but where delivery catheter 1840 has not engaged atissue 1850, any gas, liquid, and/or particulate(s) delivered bydelivery catheter 1840 may be aspirated by one or more vacuum ports1870. In a situation where skirt 1830 and delivery catheter 1840 haveeffectively engaged a tissue 1850, most, if not all, of any gas, liquid,and/or particulate(s) delivered by delivery catheter 1840 to tissue 1850would not be aspirated by one or more vacuum ports 1870 as the placementof delivery catheter 1840 on or within tissue 1850 would provide directdelivery at or within tissue 1850.

An exemplary embodiment of a system and/or device for engaging a tissueas described herein is shown in FIG. 19. As shown in FIG. 19, anexemplary apparatus shows a sleeve 1800 which has been moved in thedirection of the arrow to reveal skirt 1830 at the distal end ofengagement catheter 1810, allowing skirt to resume an expanded,frusto-conical configuration. As shown in this embodiment, deliverycatheter 1840 has been introduced at the proximal end of the apparatus(in the direction shown by the dashed arrow), allowing delivery catheter1840 to exit out of a delivery lumen (not shown) at the distal end ofengagement catheter 1840. A needle 1890 may be present at the distal endof delivery catheter 1840, facilitating the potential puncture of atissue (not shown) to allow the distal end of delivery catheter 1840 toenter a tissue.

In addition, and as shown in the exemplary embodiment of FIG. 19, a lead1900 may be introduced into delivery catheter 1840 (in the directionshown by the dashed arrow), whereby the distal end of lead 1900 may exitan aperture of needle 1890 and optionally enter a tissue and/or a lumenof a tissue. As described herein, any number of suitable types of leads1900 may be used with the delivery catheters described herein, includingsensing leads and/or pacing leads. A vacuum source 1910 may also providea source of vacuum to such an apparatus to allow skirt 1830 to engage atissue using suction.

The exemplary embodiment of an apparatus for engaging a tissue as shownin FIG. 19 comprises an engagement catheter 1810 having a curvature.Such a curved engagement catheter 1810 allows a user of such anapparatus, for example, to insert a portion of the apparatus into a bodyor tissue from one direction, and engage a tissue with skirt 1830,delivery catheter 1840, needle 1890, and/or lead 1900 from anotherdirection. For example, a user may introduce a portion of an apparatusfrom one side of the heart, and the apparatus may engage the heart froma different direction than the direction of introduction of theapparatus.

It can also be appreciated that an exemplary embodiment of an apparatusof the present disclosure may be used to engage an internal portion ofan organ. As previously referenced herein, such an apparatus may be usedto engage the surface of a tissue. However, it can be appreciated thatsuch a tissue may be an outer surface of any number of tissues,including, but not limited to, a heart, lungs, intestine, stomach, orany number of other organs or tissues. It can also be appreciated thatsome of these types of organs or tissues, including the heart forexample, may have one or more internal tissue surfaces capable of beingengaged by an apparatus of the present disclosure. For example, a userof such an apparatus may use the apparatus to engage the septum of theheart dividing one side of the heart from another. Such use mayfacilitate the delivery of a gas, liquid, and/or particulate(s) to aparticular side of the heart, as such a targeted delivery may providebeneficial effects, including, but not limited to, the ability todeliver a lead to pace the inner wall of the left side of the heart.

Referring now to FIGS. 20A, 20B, and 20C, embodiments of a portion of anapparatus for engaging a tissue according to the present disclosure areshown. As shown in FIG. 20A, an exemplary embodiment of a portion of anapparatus for engaging a tissue comprises sleeve 1800 slidingly engagingengagement catheter 1810, and when sleeve 1800 is slid in the directionof the arrow shown, skirt 1830 is revealed, having an expanded,optionally frusto-conical configuration as shown. Delivery catheter 1840may exit out of a delivery lumen (not shown), with needle 1890 presentat the distal end of delivery catheter 1840. As shown in the embodimentof FIG. 20A, lead 1900 is present, exiting out of an aperture of needle1890.

FIGS. 20B and 20C show a closer view of an embodiment of a portion of anapparatus for engaging a tissue according to the present disclosure thanis shown in FIG. 20A. As shown in FIGS. 20B and 20C, aperture 1920 ofneedle 1890 is shown, and as shown in FIG. 20C, lead 1900 may exitaperture 1920 of needle 1890.

Referring now to FIGS. 5A, 5B, 5C, and 5D, there is shown anotherembodiment of an engagement catheter as disclosed herein. Engagementcatheter 700 is an elongated tube having a proximal end 710 and a distalend 720, as well as two lumens 730, 740 extending between proximal end710 and distal end 720. Lumens 730, 740 are formed by concentric innerwall 750 and outer wall 760, as particularly shown in FIGS. 5B and 5C.At proximal end 710, engagement catheter 700 includes a vacuum port 770,which is attached to lumen 730 so that a vacuum source can be attachedto vacuum port 770 to create suction in lumen 730, thereby forming asuction channel. At distal end 720 of catheter 700, a suction port 780is attached to lumen 730 so that suction port 780 can be placed incontact with heart tissue 775 (see FIG. 5D) for aspirating the tissue,thereby forming a vacuum seal between suction port 780 and tissue 775when the vacuum source is attached and engaged. The vacuum seal enablessuction port 780 to grip, stabilize, and retract tissue 775. Forexample, attaching a suction port to an interior atrial wall using avacuum source enables the suction port to retract the atrial wall fromthe pericardial sac surrounding the heart, which enlarges thepericardial space between the atrial wall and the pericardial sac.

As shown in FIG. 5C, two internal lumen supports 810, 820 are locatedwithin lumen 730 and are attached to inner wall 750 and outer wall 760to provide support to the walls. These lumen supports divide lumen 730into two suction channels. Although internal lumen supports 810, 820extend from distal end 720 of catheter 700 along a substantial portionof the length of catheter 700, internal lumen supports 810, 820 may ormay not span the entire length of catheter 700. Indeed, as shown inFIGS. 5A, 5B, and 5C, internal lumen supports 810, 820 do not extend toproximal end 710 to ensure that the suction from the external vacuumsource is distributed relatively evenly around the circumference ofcatheter 700. Although the embodiment shown in FIG. 5C includes twointernal lumen supports, other embodiments may have just one internalsupport or even three or more such supports.

FIG. 5D shows engagement catheter 700 approaching heart tissue 775 forattachment thereto. It is important for the clinician performing theprocedure to know when the suction port has engaged the tissue of theatrial wall or the atrial appendage. For example, in reference to FIG.5D, it is clear that suction port 780 has not fully engaged tissue 775such that a seal is formed. However, because suction port 780 is notusually seen during the procedure, the clinician may determine when theproper vacuum seal between the atrial tissue and the suction port hasbeen made by monitoring the amount of blood that is aspirated, bymonitoring the suction pressure with a pressure sensor/regulator, orboth. For example, as engagement catheter 700 approaches the atrial walltissue (such as tissue 775) and is approximately in position, thesuction can be activated through lumen 730. A certain level of suction(e.g., 10 mmHg) can be imposed and measured with a pressuresensor/regulator. As long as catheter 700 does not engage the wall, someblood will be aspirated into the catheter and the suction pressure willremain the same. However, when catheter 700 engages or attaches to thewall of the heart (depicted as tissue 775 in FIG. 5D), minimal blood isaspirated and the suction pressure will start to gradually increase.Each of these signs can alert the clinician (through alarm or othermeans) as an indication of engagement. The pressure regulator is thenable to maintain the suction pressure at a preset value to preventover-suction of the tissue.

An engagement catheter, such as engagement catheter 700, may beconfigured to deliver a fluid or other substance to tissue on the insideof a wall of the heart, including an atrial wall or a ventricle wall.For example, lumen 740 shown in FIGS. 5A and 5C includes an injectionchannel 790 at distal end 720. Injection channel 790 dispenses to thetargeted tissue a substance flowing through lumen 740. As shown in FIG.5D, injection channel 790 is the distal end of lumen 740. However, inother embodiments, the injection channel may be ring-shaped (see FIG.2C) or have some other suitable configuration.

Substances that can be locally administered with an engagement catheterinclude preparations for gene or cell therapy, drugs, and adhesives thatare safe for use in the heart. The proximal end of lumen 740 has a fluidport 800, which is capable of attachment to an external fluid source forsupply of the fluid to be delivered to the targeted tissue. Indeed,after withdrawal of a needle from the targeted tissue, as discussedherein, an adhesive may be administered to the targeted tissue by theengagement catheter for sealing the puncture wound left by the needlewithdrawn from the targeted tissue.

Referring now to FIGS. 6A, 6B, and 6C, there is shown a deliverycatheter 850 comprising an elongated hollow tube 880 having a proximalend 860, a distal end 870, and a lumen 885 along the length of thecatheter. Extending from distal end 870 is a hollow needle 890 incommunication with lumen 885. Needle 890 is attached to distal end 870in the embodiment of FIGS. 6A, 6B, and 6C, but, in other embodiments,the needle may be removably attached to, or otherwise located at, thedistal end of the catheter (see FIG. 1A). In the embodiment shown inFIGS. 6A, 6B, and 6C, as in certain other embodiments having an attachedneedle, the junction (i.e., site of attachment) between hollow tube 880and needle 890 forms a security notch 910 circumferentially aroundneedle 890 to prevent needle 890 from over-perforation. Thus, when aclinician inserts needle 890 through an atrial wall to gain access tothe pericardial space, the clinician will not, under normal conditions,unintentionally perforate the pericardial sac with needle 890 becausethe larger diameter of hollow tube 880 (as compared to that of needle890) at security notch 910 hinders further needle insertion. Althoughsecurity notch 910 is formed by the junction of hollow tube 880 andneedle 890 in the embodiment shown in FIGS. 6A, 6B, and 6C, otherembodiments may have a security notch that is configured differently.For example, a security notch may include a band, ring, or similardevice that is attached to the needle a suitable distance from the tipof the needle. Like security notch 910, other security notch embodimentshinder insertion of the needle past the notch itself by presenting alarger profile than the profile of the needle such that the notch doesnot easily enter the hole in the tissue caused by entry of the needle.

It is useful for the clinician performing the procedure to know when theneedle has punctured the atrial tissue. This can be done in severalways. For example, the delivery catheter can be connected to a pressuretransducer to measure pressure at the tip of the needle. Because thepressure is lower and much less pulsatile in the pericardial space thanin the atrium, the clinician can recognize immediately when the needlepasses through the atrial tissue into the pericardial space.

Alternatively, as shown in FIG. 6B, needle 890 may be connected to astrain gauge 915 as part of the catheter assembly. When needle 890contacts tissue (not shown), needle 890 will be deformed. Thedeformation will be transmitted to strain gauge 915 and an electricalsignal will reflect the deformation (through a classical wheatstonebridge), thereby alerting the clinician. Such confirmation of thepuncture of the wall can prevent over-puncture and can provideadditional control of the procedure.

In some embodiments, a delivery catheter, such as catheter 850 shown inFIGS. 6A, 6B, and 6C, is used with an engagement catheter, such ascatheter 700 shown in FIGS. 5A, 5B, 5C, and 5D, to gain access to thepericardial space between the heart wall and the pericardial sac. Forexample, engagement catheter 700 may be inserted into the vascularsystem and advanced such that the distal end of the engagement catheteris within the atrium. The engagement catheter may be attached to thetargeted tissue on the interior of a wall of the atrium using a suctionport as disclosed herein. A standard guide wire may be inserted throughthe lumen of the delivery catheter as the delivery catheter is insertedthrough the inner lumen of the engagement catheter, such as lumen 740shown in FIGS. 5B and 5C. Use of the guide wire enables more effectivenavigation of the delivery catheter 850 and prevents the needle 890 fromdamaging the inner wall 750 of the engagement catheter 700. When the tipof the delivery catheter with the protruding guide wire reaches theatrium, the wire is pulled back, and the needle is pushed forward toperforate the targeted tissue. The guide wire is then advanced throughthe perforation into the pericardial space, providing access to thepericardial space through the atrial wall.

Referring again to FIGS. 6A, 6B, and 6C, lumen 885 of delivery catheter850 may be used for delivering fluid into the pericardial space afterneedle 890 is inserted through the atrial wall or the atrial appendage.After puncture of the wall or appendage, a guide wire (not shown) may beinserted through needle lumen 900 into the pericardial space to maintainaccess through the atrial wall or appendage. Fluid may then beintroduced to the pericardial space in a number of ways. For example,after the needle punctures the atrial wall or appendage, the needle isgenerally withdrawn. If the needle is permanently attached to thedelivery catheter, as in the embodiment shown in FIGS. 6A and 6B, thendelivery catheter 850 would be withdrawn and another delivery catheter(without an attached needle) would be introduced over the guide wireinto the pericardial space. Fluid may then be introduced into thepericardial space through the lumen of the second delivery catheter.

In some embodiments, however, only a single delivery catheter is used.In such embodiments, the needle is not attached to the deliverycatheter, but instead may be a needle wire (see FIG. 1A). In suchembodiments, the needle is withdrawn through the lumen of the deliverycatheter, and the delivery catheter may be inserted over the guide wireinto the pericardial space. Fluid is then introduced into thepericardial space through the lumen of the delivery catheter.

The various embodiments disclosed herein may be used by clinicians, forexample: (1) to deliver genes, cells, drugs, etc.; (2) to providecatheter access for epicardial stimulation; (3) to evacuate fluidsacutely (e.g., in cases of pericardial tamponade) or chronically (e.g.,to alleviate effusion caused by chronic renal disease, cancer, etc.);(4) to perform transeptal puncture and delivery of a catheter throughthe left atrial appendage for electrophysiological therapy, biopsy,etc.; (5) to deliver a magnetic glue or ring through the right atrialappendage to the aortic root to hold a percutaneous aortic valve inplace; (6) to deliver a catheter for tissue ablation, e.g., to thepulmonary veins, or right atrial and epicardial surface of the heart foratrial and ventricular arrythmias; (7) to deliver and place epicardial,right atrial, and right and left ventricle pacing leads (as discussedherein); (8) to occlude the left atrial appendage through percutaneousapproach; and (9) to visualize the pericardial space with endo-camera orscope to navigate the epicardial surface of the heart for therapeuticdelivery, diagnosis, lead placement, mapping, etc. Many otherapplications, not explicitly listed here, are also possible and withinthe scope of the present disclosure.

Referring now to FIG. 7, there is shown a delivery catheter 1000.Delivery catheter 1000 includes an elongated tube 1010 having a wall1020 extending from a proximal end (not shown) of tube 1010 to a distalend 1025 of tube 1010. Tube 1010 includes two lumens, but otherembodiments of delivery catheters may have fewer than, or more than, twolumens, depending on the intended use of the delivery catheter. Tube1010 also includes a steering channel 1030, in which a portion ofsteering wire system 1040 is located. Steering channel 1030 formsorifice 1044 at distal end 1025 of tube 1010 and is sized to fit over aguide wire 1050.

FIG. 8 shows in more detail steering wire system 1040 within steeringchannel 1030 (which is shown cut away from the remainder of the deliverycatheter). Steering wire system 1040 is partially located in steeringchannel 1030 and comprises two steering wires 1060 and 1070 and acontroller 1080, which, in the embodiment shown in FIG. 8, comprises afirst handle 1090 and a second handle 1094. First handle 1090 isattached to proximal end 1064 of steering wire 1060, and second handle1094 is attached to proximal end 1074 of steering wire 1070. Distal end1066 of steering wire 1060 is attached to the wall of the tube of thedelivery catheter within steering channel 1030 at attachment 1100, anddistal end 1076 of steering wire 1070 is attached to the wall of thetube of the delivery catheter within steering channel 1030 at attachment1110. As shown in FIG. 7, attachment 1100 and attachment 1110 arelocated on opposing sides of steering channel 1030 near distal tip 1120of delivery catheter 1000.

In the embodiment of FIG. 8, steering wires 1060 and 1070 are threadedas a group through steering channel 1030. However, the steering wiresystems of other embodiments may include steering wires that areindividually threaded through smaller lumens within the steeringchannel. For example, FIG. 11 shows a cross-sectional view of a deliverycatheter 1260 having an elongated tube 1264 comprising a wall 1266, asteering channel 1290, a first lumen 1270, and a second lumen 1280.Delivery catheter 1260 further includes a steering wire 1292 within asteering wire lumen 1293, a steering wire 1294 within a steering wirelumen 1295, and a steering wire 1296 within a steering wire lumen 1297.Each of steering wire lumens 1293, 1295, and 1297 is located withinsteering channel 1290 and is formed from wall 1266. Each of steeringwires 1292, 1294, and 1296 is attached to wall 1266 within steeringchannel 1290. As will be explained, the attachment of each steering wireto the wall may be located near the distal tip of the delivery catheter,or may be located closer to the middle of the delivery catheter.

Referring now to FIGS. 7 and 8, steering wire system 1040 can be used tocontrol distal tip 1120 of delivery catheter 1000. For example, whenfirst handle 1090 is pulled, steering wire 1060 pulls distal tip 1120,which bends delivery catheter 1000, causing tip deflection in a firstdirection. Similarly, when second handle 1094 is pulled, steering wire1070 pulls distal tip 1120 in the opposite direction, which bendsdelivery catheter 1000, causing tip deflection in the oppositedirection. Thus, delivery catheter 1000 can be directed (i.e., steered)through the body using steering wire system 1040.

Although steering wire system 1040 has only two steering wires, otherembodiments of steering wire systems may have more than two steeringwires. For example, some embodiments of steering wire systems may havethree steering wires (see FIG. 11), each of which is attached to thesteering channel at a different attachment. Other embodiments ofsteering wire systems may have four steering wires. Generally, moresteering wires give the clinician more control for directing thedelivery catheter because each additional steering wire enables the userto deflect the tip of the delivery catheter in an additional direction.For example, four steering wires could be used to direct the deliverycatheter in four different directions (e.g., up, down, right, and left).

If a steering wire system includes more than two steering wires, thedelivery catheter may be deflected at different points in the samedirection. For instance, a delivery catheter with three steering wiresmay include two steering wires for deflection in a certain direction anda third steering wire for reverse deflection (i.e., deflection in theopposite direction). In such an embodiment, the two steering wires fordeflection are attached at different locations along the length of thedelivery catheter. Referring now to FIGS. 9A-9C, there is shown asteering wire system 1350 within steering channel 1360 (which is showncut away from the remainder of the delivery catheter) in differentstates of deflection. Steering wire system 1350 is partially located insteering channel 1360 and comprises three steering wires 1370, 1380, and1390 and a controller 1400, which, in the embodiment shown in FIGS.9A-9C, comprises a handle 1405. Handle 1405 is attached to proximal end1374 of steering wire 1370, proximal end 1384 of steering wire 1380, andproximal end 1394 of steering wire 1390. Distal end 1376 of steeringwire 1370 is attached to the wall of the tube of the delivery catheterwithin steering channel 1360 at attachment 1378, which is near thedistal tip of the delivery catheter (not shown). Distal end 1386 ofsteering wire 1380 is attached to the wall of the tube of the deliverycatheter within steering channel 1360 at attachment 1388, which is nearthe distal tip of the delivery catheter (not shown). Attachment 1378 andattachment 1388 are located on opposing sides of steering channel 1360such that steering wires 1370 and 1380, when tightened (as explainedbelow), would tend to deflect the delivery catheter in oppositedirections. Distal end 1396 of steering wire 1390 is attached to thewall of the tube of the delivery catheter within steering channel 1360at attachment 1398, which is located on the delivery catheter at a pointcloser to the proximal end of the delivery catheter than attachments1378 and 1388. Attachment 1398 is located on the same side of steeringchannel 1360 as attachment 1388, such that steering wires 1380 and 1390,when tightened (as explained below), would tend to deflect the deliverycatheter in the same direction. However, because attachment 1398 iscloser to the proximal end of the delivery catheter than is attachment1388, the tightening of steering wire 1390 tends to deflect the deliverycatheter at a point closer to the proximal end of the delivery catheterthan does the tightening of steering wire 1380. Thus, as shown in FIG.9A, the tightening of steering wire 1390 causes a deflection in thedelivery catheter approximately at point 1410. The tightening ofsteering wire 1380 at the same time causes a further deflection in thedelivery catheter approximately at point 1420, as shown in FIG. 9B. Thetightening of steering wire 1370, therefore, causes a reversedeflection, returning the delivery catheter to its original position(see FIG. 9C).

Referring again to FIG. 7, elongated tube 1010 further includes lumen1130 and lumen 1140. Lumen 1130 extends from approximately the proximalend (not shown) of tube 1010 to or near distal end 1025 of tube 1010.Lumen 1130 has a bend 1134, relative to tube 1010, at or near distal end1025 of tube 1010 and an outlet 1136 through wall 1020 of tube 1010 ator near distal end 1025 of tube 1010. Similarly, lumen 1140 has a bend1144, relative to tube 1010, at or near distal end 1025 of tube 1010 andan outlet 1146 through wall 1020 of tube 1010 at or near distal end 1025of tube 1010. In the embodiment shown in FIG. 7, lumen 1130 isconfigured as a laser Doppler tip, and lumen 1140 is sized to accept aretractable sensing lead 1150 and a pacing lead 1160 having a tip at thedistal end of the lead. The fiberoptic laser Doppler tip detects andmeasures blood flow (by measuring the change in wavelength of lightemitted by the tip), which helps the clinician to identify—and thenavoid—blood vessels during lead placement. Sensing lead 1150 is designedto detect electrical signals in the heart tissue so that the cliniciancan avoid placing a pacing lead into electrically nonresponsive tissue,such as scar tissue. Pacing lead 1160 is a screw-type lead for placementonto the cardiac tissue, and its tip, which is an electrode, has asubstantially screw-like shape. Pacing lead 1160 is capable of operativeattachment to a CRT device (not shown) for heart pacing. Although lead1160 is used for cardiac pacing, any suitable types of leads may be usedwith the delivery catheters described herein, including sensing leads.

Each of bend 1134 of lumen 1130 and bend 1144 of lumen 1140 forms anapproximately 90-degree angle, which allows respective outlets 1136 and1146 to face the external surface of the heart as the catheter ismaneuvered in the pericardial space. However, other embodiments may havebends forming other angles, smaller or larger than 90-degrees, so longas the lumen provides proper access to the external surface of the heartfrom the pericardial space. Such angles may range, for example, fromabout 25-degrees to about 155-degrees. In addition to delivering leadsand Doppler tips, lumen 1130 and lumen 1140 may be configured to allow,for example, the taking of a cardiac biopsy, the delivery of gene celltreatment or pharmacological agents, the delivery of biological glue forventricular reinforcement, implementation of ventricular epicardialsuction in the acute myocardial infarction and border zone area, theremoval of fluid in treatment of pericardial effusion or cardiactamponade, or the ablation of cardiac tissue in treatment of atrialfibrillation.

For example, lumen 1130 could be used to deliver a catheter needle forintramyocardial injection of gene cells, stems, biomaterials, growthfactors (such as cytokinase, fibroblast growth factor, or vascularendothelial growth factor) and/or biodegradable synthetic polymers,RGD-liposome biologic glue, or any other suitable drug or substance fortreatment or diagnosis. For example, suitable biodegradable syntheticpolymer may include polylactides, polyglycolides, polycaprolactones,polyanhydrides, polyamides, and polyurethanes. In certain embodiments,the substance comprises a tissue inhibitor, such as a metalloproteinase(e.g., metalloproteinase 1).

The injection of certain substances (such as biopolymers andRGD-liposome biologic glue) is useful in the treatment of chronic heartfailure to reinforce and strengthen the left ventricular wall. Thus,using the embodiments disclosed herein, the injection of such substancesinto the cardiac tissue from the pericardial space alleviates theproblems and risks associated with delivery via the transthoracicapproach. For instance, once the distal end of the delivery catheter isadvanced to the pericardial space, as disclosed herein, a needle isextended through a lumen of the delivery catheter into the cardiactissue and the substance is injected through the needle into the cardiactissue.

The delivery of substances into the cardiac tissue from the pericardialspace can be facilitated using a laser Doppler tip. For example, whentreating ventricular wall thinning, the laser Doppler tip located inlumen 1140 of the embodiment shown in FIG. 7 can be used to measure thethickness of the left ventricular wall during the procedure (in realtime) to determine the appropriate target area for injection.

Referring again to FIG. 8, although controller 1080 comprises firsthandle 1090 and second handle 1094, other embodiments of the controllermay include different configurations. For example, instead of usinghandles, a controller may include any suitable torque system forcontrolling the steering wires of the steering wire system. Referringnow to FIG. 10, there is shown a portion of a steering wire system 1170having steering wire 1180, steering wire 1190, and controller 1200.Controller 1200 comprises a torque system 1210 having a first rotatablespool 1220, which is capable of collecting and dispensing steering wire1180 upon rotation. For example, when first rotatable spool 1220 rotatesin a certain direction, steering wire 1180 is collected onto spool 1220,thereby tightening steering wire 1180. When spool 1220 rotates in theopposite direction, steering wire 1180 is dispensed from spool 1220,thereby loosening steering wire 1180. Torque system 1210 also has asecond rotatable spool 1230, which is capable of collecting anddispensing steering wire 1190 upon rotation, as described above.

Torque system 1210 further includes a first rotatable dial 1240 and asecond rotatable dial 1250. First rotatable dial 1240 is attached tofirst rotatable spool 1220 such that rotation of first rotatable dial1240 causes rotation of first rotatable spool 1220. Similarly, secondrotatable dial 1250 is attached to second rotatable spool 1230 such thatrotation of second rotatable dial 1250 causes rotation of secondrotatable spool 1230. For ease of manipulation of the catheter, torquesystem 1210, and specifically first and second rotatable dials 1240 and1250, may optionally be positioned on a catheter handle (not shown) atthe proximal end of tube 1010.

Steering wire system 1170 can be used to direct a delivery catheterthrough the body in a similar fashion as steering wire system 1140.Thus, for example, when first rotatable dial 1240 is rotated in a firstdirection (e.g., clockwise), steering wire 1180 is tightened and thedelivery catheter is deflected in a certain direction. When firstrotatable dial 1240 is rotated in the other direction (e.g.,counterclockwise), steering wire 1180 is loosened and the deliverycatheter straightens to its original position. When second rotatabledial 1250 is rotated in one direction (e.g., counterclockwise), steeringwire 1190 is tightened and the delivery catheter is deflected in adirection opposite of the first deflection. When second rotatable dial1250 is rotated in the other direction (e.g., clockwise), steering wire1190 is loosened and the delivery catheter is straightened to itsoriginal position.

Certain other embodiments of steering wire system may comprise othertypes of torque system, so long as the torque system permits theclinician to reliably tighten and loosen the various steering wires. Themagnitude of tightening and loosening of each steering wire should becontrollable by the torque system.

Referring again to FIG. 11, there is shown a cross-sectional view ofdelivery catheter 1260. Delivery catheter 1260 includes tube 1265, afirst lumen 1270, a second lumen 1280, and a steering channel 1290.Steering wires 1292, 1294, and 1296 are shown within steering channel1290. First lumen 1270 has outlet 1275, which can be used to deliver amicro-camera system (not shown) or a laser Doppler tip 1278. Secondlumen 1280 is sized to deliver a pacing lead 1300, as well as a sensinglead (not shown).

Treatment of cardiac tamponade, by the removal of a pericardialeffusion, may be accomplished using an apparatus of the presentdisclosure as described below. A typical procedure would involve thepercutaneous intravascular insertion of a portion of an apparatus into abody, which can be performed under local or general anesthesia. Aportion of the apparatus may then utilize an approach described hereinor otherwise known by a user of the apparatus to enter the percutaneousintravascular pericardial sac. It can be appreciated that such anapparatus may be used to access other spaces within a body to removefluid and/or deliver a gas, liquid, and/or particulate(s) as describedherein, and that such an apparatus is not limited to heart access andremoval of pericardial effusions.

Exemplary embodiments of a portion of such an apparatus are shown inFIGS. 21A and 21B. As shown in FIG. 21A, a perforated drainage catheter2100 is provided. Perforated drainage catheter 2100 comprises a tubedefining at least one suction/infusion aperture 2110, and as shown inthe embodiment in FIG. 21A, perforated drainage catheter 2100 definesmultiple suction/infusion apertures 2110. Suction/infusion apertures2110 are operably connected to an internal lumen defined withinperforated delivery catheter 2100. It can be appreciated that theportion of perforated drainage catheter 2100 as shown in FIGS. 21A and21B may be coupled to one or more portions of a system for engaging atissue as described herein. As such, one or more portions of a systemfor engaging a tissue may be used to define a system for removing fluidas described herein.

It can be appreciated that the internal lumen within perforated deliverycatheter 2100 may define multiple internal channels. For example,perforated delivery catheter 2100 may define two channels, one channeloperably coupled to one or more suction/infusion apertures 2110 to allowfor a vacuum source coupled to one end of the channel to provide suctionvia the suction/infusion apertures 2110, and one channel operablycoupled to one or more other suction/infusion channels to allow for theinjection of gas, liquid, and/or particulate(s) to a target site.

As described in further detail below, when perforated drainage catheter2100 enters a space in a body, for example a pericardial sac, perforateddrainage catheter 2100 may be used to remove fluid by the use of suctionthrough one or more suction/infusion apertures 2110. Perforated drainagecatheter 2100 may also be used to deliver gas, liquid, and/orparticulate(s) to a target site through one or more suction/infusionapertures 2110.

Another exemplary embodiment of a portion of a perforated drainagecatheter 2100 is shown in FIG. 21B. As shown in FIG. 21B, perforateddrainage catheter 2100 comprises a tube with multiple suction/infusionapertures 2110. However, in this exemplary embodiment, perforateddrainage catheter 2100 comprises a number of concave grooves 2120extending a portion of a length of perforated drainage catheter 2100,whereby the suction/infusion apertures 2110 are provided at the recessedportions therein. Concave grooves 2120, when positioned at leastpartially around the circumference of perforated drainage catheter 2100,define one or more ridges 2130 extending a portion of a length ofperforated drainage catheter 2100. Said ridges 2130 of perforateddrainage catheter 2100, when positioned at or near a tissue (not shown),aid to prevent a tissue from coming in direct contact with one or moresuction/infusion apertures 2110. For example, when perforated drainagecatheter 2100 is used in a manner described herein and when a vacuum iscoupled to perforated drainage catheter 2100, suction from one or moresuction/infusion apertures 2110 positioned within one or more concavegrooves 2120 would allow for the removal of fluid present in the area ofperforated drainage catheter 2100. Ridges 2130 would aid to prevent orminimize tissue adhesion and/or contact with the one or moresuction/infusion apertures 2110.

A procedure using perforated drainage catheter 2100 may be performed byinserting perforated drainage catheter 2100 into a pericardial sac,following the cardiac surface using, for example, fluoroscopy and/orechodoppler visualization techniques. When perforated drainage catheter2100 is inserted into a pericardial sac, a pericardial effusion presentwithin the pericardial sac, may be removed by, for example, gentlesuction using a syringe. In one example, a 60 cc syringe may be used toremove the effusion with manual gentle suction. When the effusion hasbeen removed, the patients hemodynamic parameters may be monitored todetermine the effectiveness of the removal of the effusion. When thepericardial sac is empty, determined by, for example, fluoroscopy orechodoppler visualization, the acute pericardial effusion catheter maybe removed, or it may be used for local treatment to introduce, forexample, an antibiotic, chemotherapy, or another drug as describedbelow.

An exemplary embodiment of a portion of a perforated drainage catheter2100 present within a pericardial sac is shown in FIG. 22. As shown inFIG. 22, perforated drainage catheter 2100 is first inserted into theheart 2200 using one or more of the techniques and/or proceduresdescribed herein, and is placed through the right atrial appendage 2210,the visceral pericardium 2215, and into the pericardial sac 2220. Theouter portion of the pericardial sac 2220 is defined by the parietalpericardium 2230. A pericardial effusion 2240 (fluid within thepericardial sac 2220) may then be removed using perforated drainagecatheter 2100. When a vacuum source (not shown) is coupled to theproximal end of a portion of a system for removing fluid (comprising, inpart, perforated drainage catheter 2100 and one or more other componentsof a system for engaging a tissue as described herein), the introductionof a vacuum to perforated drainage catheter 2100 allows the pericardialeffusion 2240 (the fluid) to be withdrawn from the pericardial sac 2220into one or more suction/infusion apertures 2110 defined along a lengthof suction/infusion apertures 2110.

When perforated drainage catheter 2100 is used to remove some or all ofa pericardial effusion (or other fluid present within a space within abody), it may also be used to deliver a gas, liquid, and/orparticulate(s) at or near the space where the fluid was removed. Forexample, the use of perforated drainage catheter 2100 to remove apericardial effusion may increase the risk of infection. As such,perforated drainage catheter 2100 may be used to rinse the pericardialsac (or other space present within a body) with water and/or any numberof beneficial solutions, and may also be used to deliver one or moreantibiotics to provide an effective systemic antibiotic therapy for thepatient. While the intrapericardial instillation of antibiotics (e.g.,gentamycin) is useful, it is typically not sufficient by itself, and assuch, it may be combined with general antibiotics treatment for a moreeffective treatment.

Additional methods to treat neoplastic pericardial effusions withouttamponade may be utilized using a device, system and/or method of thepresent disclosure. For example, a systemic antineoplastic treatment maybe performed to introduce drugs to inhibit and/or prevent thedevelopment of tumors. If a non-emergency condition exists (e.g., not acardiac tamponade), a system and/or method of the present disclosure maybe used to perform a pericardiocentesis. In addition, the presentdisclosure allows for the intrapericardial instillation of acytostatic/sclerosing agent. It can be appreciated that using one ormore of the devices, systems and/or methods disclosed herein, theprevention of recurrences may be achieved by intrapericardialinstillation of sclerosing agents, cytotoxic agents, orimmunomodulators, noting that the intrapericardial treatment may betailored to the type of the tumor. Regarding chronic autoreactivepericardial effusions, the intrapericardial instillation of crystalloidglucocorticoids could avoid systemic side effects, while still allowinghigh local dose application.

A pacing lead may be placed on the external surface of the heart usingan engagement catheter and a delivery catheter as disclosed herein. Forexample, an elongated tube of an engagement catheter is extended into ablood vessel so that the distal end of the tube is in contact with atargeted tissue on the interior of a wall of the heart. As explainedabove, the targeted tissue may be on the interior of the atrial wall orthe atrial appendage. Suction is initiated to aspirate a portion of thetargeted tissue to retract the cardiac wall away from the pericardialsac that surrounds the heart, thereby enlarging a pericardial spacebetween the pericardial sac and the cardiac wall. A needle is theninserted through a lumen of the tube and advanced to the heart. Theneedle is inserted into the targeted tissue, causing a perforation ofthe targeted tissue. The distal end of a guide wire is inserted throughthe needle into the pericardial space to secure the point of entrythrough the cardiac wall. The needle is then withdrawn from the targetedtissue.

A delivery catheter, as described herein, is inserted into the lumen ofthe tube of the engagement catheter and over the guide wire. Thedelivery catheter may be a 14 Fr, radiopaque steering catheter. Thedistal end of the delivery catheter is advanced over the guide wirethrough the targeted tissue into the pericardial space. Once in thepericardial space, the delivery catheter is directed using a steeringwire system as disclosed herein. In addition, a micro-camera system maybe extended through the lumen of the delivery catheter to assist in thedirection of the delivery catheter to the desired location in thepericardial space. Micro-camera systems suitable for use with thedelivery catheter are well-known in the art. Further, a laser Dopplersystem may be extended through the lumen of the delivery catheter toassist in the direction of the delivery catheter. The delivery catheteris positioned such that the outlet of one of the lumens of the deliverycatheter is adjacent to the external surface of the heart (e.g., theexternal surface of an atrium or a ventricle). A pacing lead is extendedthrough the lumen of the delivery catheter onto the external surface ofthe heart. The pacing lead may be attached to the external surface ofthe heart, for example, by screwing the lead into the cardiac tissue. Inaddition, the pacing lead may be placed deeper into the cardiac tissue,for example in the subendocardial tissue, by screwing the lead furtherinto the tissue. After the lead is placed in the proper position, thedelivery catheter is withdrawn from the pericardial space and the body.The guide wire is withdrawn from the pericardial space and the body, andthe engagement catheter is withdrawn from the body.

The disclosed embodiments can be used for subendocardial, as well asepicardial, pacing. While the placement of the leads is epicardial, theleads can be configured to have a long screw-like tip that reaches nearthe subendocardial wall. The tip of the lead can be made to beconducting and stimulatory to provide the pacing to the subendocardialregion. In general, the lead length can be selected to pace transmurallyat any site through the thickness of the heart wall. Those of skill inthe art can decide whether epicardial, subendocardial, or sometransmural location stimulation of the muscle is best for the patient inquestion.

The disclosure of the present application provides devices, systems, andmethods to improve healing of tissue scar, including, but not limitedto, a myocardial infarct, and to mechanically reinforce the border zonebetween viable and scar tissue to prevent dilation and failure of organ(specifically heart failure). In at least one embodiment of the presentdisclosure, the devices, systems, and methods disclosed herein areuseful to stop the remodeling of the myocardial infarct tissue andborder zone in the first days after acute event. Epicardial suction maybe used as a means to save patching areas with live myocardial cells(myocytes) inside of the infarct area. The devices, systems, and methodsof the present disclosure may also be useful to decrease the ischemicnecrotic area and stop the remodeling of the left ventricle in order todecrease evolution towards congestive heart failure.

In at least one embodiment, irrigation (blood flow) is improved byproviding topical negative pressure to an area of myocardial infarct,using, for example, a suction/infusion catheter of the presentdisclosure. An introduction of negative pressure to a target site asdisclosed herein acts to improve blood flow/circulation to an affectedarea.

In at least one embodiment, border zone reinforcement is facilitated bythe placement of viable fibroblasts at a targeted site of heart damage,whereby the fibroblasts provide the structural support to reinforce thedamaged heart tissue. The fibroblasts aid with the stiffening of themyocardial infarct and/or its border zone, with such structuralreinforcement generally aiding with the heart healing process aftermyocardial infarct. If heart tissue becomes too pliable (as is commonafter a myocardial infarction), the tissue may dilate, leading to ananeurysm (bulging of a heart wall), and if such an aneurysm ruptures, itlikely results in instant death of the patient. As such, structuralreinforcement as described herein may be useful to prevent such tissuedilation and improve a patients chances of recovery after a heartattack.

An exemplary device for promoting infarct healing is shown in FIGS. 23Aand 23B. As shown in the embodiment of FIGS. 23A and 23B, catheterassembly 2300 comprises an engagement catheter 2302, a delivery catheter2304, and a suction/infusion catheter 2306. Engagement catheter 2302 ispositioned at least partially around delivery catheter 2304, anddelivery catheter 2304 is positioned at least partially aroundsuction/infusion catheter 2306 as shown in FIGS. 23A and 23B. Engagementcatheter 2302 and/or delivery catheter 2304 may comprise one or moreengagement and/or delivery catheters known in the art. It can beappreciated that catheter assembly 2300 may comprises additional orfewer elements than those described herein, as long as catheter assembly2300 comprises suction/infusion catheter 2306 for introduction into aspace of a heart as disclosed herein.

Suction/infusion catheter 2306 comprises a proximal end (the endcontrolled by a user, not shown), a distal end 2308 (the end insertedinto a body space, including, but not limited to, a pericardial space),and one or more apertures 2310 positioned along suction/infusioncatheter 2306 at or near the distal end 2308 of suction/infusioncatheter. As shown in the embodiment of FIG. 23A, delivery catheter 2304is partially within the internal space of engagement catheter 2302 andpartially extended from engagement catheter 2302, and suction/infusioncatheter 2306 is partially within the internal space of deliverycatheter 2304 and partially extended from delivery catheter 2304. Asshown in FIG. 23B, a larger portion of suction/infusion catheter 2306 isshown extended from delivery catheter 2304.

Also, as shown in the exemplary embodiment of FIGS. 23A and 23B,suction/infusion catheter 2306 may comprise a “memory” catheter. As usedherein, the term “memory catheter” is intended to include, but is notlimited to, a type of catheter either having a first configuration thatmay be deformed while in the presence of or positioned within anotherdevice, or a type of catheter capable of having its configurationaltered by, for example, an external physical force or a change intemperature. In an exemplary embodiment, the “memory” is provided by awire positioned within the wall of suction/infusion catheter 2306.

In the embodiments shown in FIGS. 23A and 23B, suction/infusion catheter2306 comprises a memory catheter that has a first configuration(coiled), wherein the configuration is deformed (at least partiallystraightened, or uncoiled) while that particular portion ofsuction/infusion catheter 2306 is positioned within, for example, theinternal space of delivery catheter 2304. As such a suction/infusioncatheter 2306 described thereby extends from delivery catheter 2304,suction/infusion catheter 2306 (a “memory catheter” in this exemplaryembodiment) coils as more of suction/infusion catheter 2306 extends fromdelivery catheter 2304.

As shown in the exemplary embodiment of FIGS. 23A and 23B,suction/infusion catheter 2306 comprises multiple apertures 2310positioned along a length of suction/infusion catheter 2306. Saidapertures 2310 may allow a gas, fluid, particulate, or other substance,including, but not limited to, liposomes, magnetic liposomes, and/orcells, present within an internal lumen (not shown) of suction/infusioncatheter 2306 to be injected from one or more apertures 2310 ofsuction/infusion catheter. In addition, or in the alternative, saidapertures 2310 allow a gas, fluid, particulate, or other substancepresent within a body space (not shown) to enter one or more apertures2310 by way of a vacuum provided within an internal lumen (not shown) ofsuction/infusion catheter 2306 from a vacuum source (not shown).Suction/infusion catheter 2306 may comprise one lumen whereby a gas,fluid, particulate, or other substance may enter into or exit from thelumen by way of one or more apertures 2310, or suction/infusion catheter2306 may comprise two or more lumens, whereby a gas, fluid, particulate,or other substance may enter into a lumen and/or exit from the same oranother lumen by way of one or more apertures 2310.

An exemplary embodiment of a suction/infusion catheter 2306 introducedinto a pericardial space at or near a left ventricle of a heart is shownin FIG. 24. Suction/infusion catheter 2306 may be inserted into thepericardial space of a heart 2400 through any number of methods,including, but not limited to, the introduction of suction/infusioncatheter 2306 or a catheter assembly 2300 through the jugular or femoralvein to the superior or inferior vena cavae, respectively, and to theright atrial wall or atrial appendage (percutaneously) to thepericardial sac (through puncture). Entry of a suction/infusion catheter2306 into the pericardial space of the heart 2400 according to thepresent disclosure is not limited to any single method of entry. It canbe appreciated that suction/infusion catheter 2306 may be introducedinto other spaces over the surface of the heart 2400 other than a leftventricle 2402, including, but not limited to, spaces over thesurface(s) of the right ventricle, a left atrium, and a right atrium.Furthermore, it can be appreciated that suction/infusion catheter 2306may be inserted into other areas of the body, including, but not limitedto, spaces within other body organs and spaces in the body betweenorgans.

According to at least one example of entry of a suction/infusioncatheter 2306 into a left ventricle 2402 of a heart 2400, a catheterassembly 2300 is used to introduce suction/infusion catheter 2306. Asshown in FIG. 24, the “memory” of suction/infusion catheter 2306 allowsthe suction/infusion catheter 2306 to adapt a “racquet” shape whensuction/infusion catheter 2306 is delivered over the epicardial targetarea through previously disclosed atrial access. In such an exemplarymethod of entry, engagement catheter 2302 may be used to engage aportion of a body and/or organ, facilitating the delivery ofsuction/infusion catheter 2306 by way of delivery catheter 2304 asdescribed herein.

When the distal end 2308 of suction/infusion catheter 2306 has entered atargeted site, suction/infusion catheter 2306 may be extended fromdelivery catheter 2304 as shown in FIG. 24. As previously described inFIG. 23B, as suction/infusion catheter 2306 extends from deliverycatheter 2304, suction/infusion catheter may coil based upon a “memory”it comprises as described herein. As shown in FIG. 24, a portion ofsuction/infusion catheter 2306 has extended from delivery catheter 2304,whereby a portion of suction/infusion catheter 2306 has coiled over thesurface of the left ventricle 2402 of the heart 2400.

Such an exemplary delivery may be used to deliver suction/infusioncatheter 2306 at or near an area of acute myocardial infarct 2404 asshown in FIG. 24. A coiled portion of suction/infusion catheter 2306 ispositioned at or near an acute myocardial infarct 2404, and as describedin further detail herein, such a positioning allows for the delivery ofa gas, fluid, particulate, or other substance, including, but notlimited to, liposomes, magnetic liposomes, and/or cells, at or near thearea of acute myocardial infarct 2404. As such, suction/infusioncatheter 2306 may facilitate border zone reinforcement as describedherein by introducing, for example, magnetic liposomes and/or magneticcells to a target site within the heart 2400.

A suction/infusion catheter 2306 of the present disclosure may beoperable to provide suction to a target site within a heart 2400. Forexample, and as described herein, the introduction of negative pressureover the surface or epicardium of the hear 2400 may increase blood flowto a damaged area of the heart 2400 (myocardial infarct), with theimproved blood flow assisting generally with the myocardial infarcthealing process. Such suction may be introduced using a suction/infusioncatheter 2306 of the present disclosure when suction/infusion catheter2306 is either directly or indirectly coupled to a source of vacuum. Asource of vacuum comprising a controlled pressure suction console mayprovide intermittent or continuous suction at different pressures and/ortimes as desired.

In addition, suction/infusion catheter 2306 may also be used to remove agas, fluid, particulate, or other substance, from an area within a bodyvia one or more apertures 2310 present along suction/infusion catheter2306. Suction/infusion catheter 2306 may be positioned at or near anacute myocardial infarct 2404 at least partially within a border zone2406 surrounding the acute myocardial infarct 2404 as shown in FIG. 24.

Exemplary embodiments of delivery catheters 2304 with multiplesuction/infusion catheters 2306 are shown in FIGS. 25A, 25B, and 25C. Asshown in FIG. 25A, two suction/infusion catheters 2306 are shownpartially extended from delivery catheter 2304. In at least oneexemplary embodiment, a guide wire 2500 may be positioned at or near thedistal end of at least one suction/infusion catheter 2306 to assist anuser with positioning suction/infusion catheter(s) 2306 within a spacein a body.

FIG. 25A shows one suction/infusion catheter 2306 extending somewhatfurther from delivery catheter 2304 than the other suction/infusioncatheter 2306. FIG. 25B shows an exemplary embodiment of deliverycatheter 2304 having two suction/infusion catheters 2306 extending atleast partially therefrom. One of the two suction/infusion catheters2306 is shown in a coiled configuration based upon a “memory” asdescribed herein. FIG. 25C shows an exemplary embodiment of deliverycatheter 2304 having two suction/infusion catheters 2306 extending atleast partially therefrom, with the two suction/infusion catheters 2306having coiled configurations. The dashed line portion of one of thesuction/infusion catheters 2306 shown in FIG. 25C is to show an exampleof how the suction/infusion catheter 2306 may coil as it further extendsfrom delivery catheter 2304.

The suction/infusion catheters 2306 shown in FIGS. 25A, 25B, and 25Ccomprise one or more apertures 2310 positioned along one or more of thesuction/infusion catheters 2306 of a multiple suction/infusion catheter2306 assembly. It can be appreciated that embodiments of catheterassemblies 2300 and/or suction/infusion catheters 2306 described hereinare not limited to any particular example or figure/drawing shownherein, and that such described embodiments are provided as examples ofcatheter assemblies 2300 and/or suction/infusion catheters 2306 of thepresent disclosure.

An embodiment of a catheter assembly 2300, or an assembly comprisingmultiple suction/infusion catheters 2306, may be positioned at or nearan area of acute myocardial infarct 2404 as shown in FIG. 26. As shownin FIG. 26, coiled portions of two suction/infusion catheters 2306 arepositioned at or near an acute myocardial infarct 2404, and as describedin further detail herein, such a positioning allows for the delivery ofa gas, fluid, particulate, or other substance, including, but notlimited to, liposomes, magnetic liposomes, and/or cells, at or near thearea of acute myocardial infarct 2404. Suction/infusion catheters 2306may also be used to remove a gas, fluid, particulate, or othersubstance, from an area within a body via one or more apertures 2310present along one or more suction/infusion catheters 2306.Suction/infusion catheters 2306 may be positioned at or near an acutemyocardial infarct 2404 at least partially within a border zone 2406surrounding the acute myocardial infarct 2404 as shown in FIG. 26.

At least one benefit to a multiple suction/infusion catheter 2306assembly would be the increased amount of suction/infusion catheter 2306surface area available at a particular target site, allowing for alarger amount of targeted delivery and/or suction as described herein.Such an increased surface area may, for example, allow for targeteddelivery of magnetic liposomes and/or magnetic cells as describedherein, or may allow for targeted suction to increase blood flow tofacilitate a damaged area of a heart 2400. For example, a catheterassembly 2300 and/or a portion of a catheter assembly 2300, as describedherein, comprising two suction/infusion catheters 2306, may allow fordelivery of substance(s) from one suction/infusion catheter 2306, andthe removal of substance(s) from the other.

As shown in FIGS. 27A and 27B, an occluder 2700 may be used with one ormore suction/infusion catheters 2306 to provide a user of asuction/infusion catheter 2306 with greater flexibility with respect totargeted delivery or targeted suction as described herein. As shown inFIG. 27A, a distal portion of a suction/infusion catheter 2306 is shownwith multiple apertures 2310 positioned along a length ofsuction/infusion catheter 2306. An occluder 2700 may be inserted into aproximal end of a suction/infusion catheter 2306 (so as to becontrollable by a user), whereby the user may position occluder 2700within a lumen within suction/infusion catheter 2306 to fully orpartially block one or more apertures 2310. As shown in the embodimentof FIG. 27A, occluder 2700 is blocking two apertures 2310, while the twoapertures 2310 closest to the distal end of suction/infusion catheter2306 remain open. As such, if suction/infusion catheter is used todeliver a substance (via space 2702 shown in FIG. 27A), the substancemay be delivered from the apertures 2310 not closed/blocked by occluder2700. Similarly, if suction/infusion catheter is used to provide suctionat a targeted site (with a vacuum provided via space 2702 shown in FIG.27A), suction may be had by the apertures 2310 not closed/blocked byoccluder 2700.

FIG. 27A also shows a optional support wire 2704 positioned within thewall of suction/infusion catheter 2306 and extending, at leastpartially, a length of suction/infusion catheter 2306. Support wire 2704may provide some rigidity to suction/infusion catheter 2306 and may alsoassist a user when using and/or introducing an occluder 2700 asdescribed herein. Support wire 2704, in addition and/or in thealternative to providing rigidity, may provide the “memory” for a memorysuction/infusion catheter 2306 as described herein.

FIG. 27B shows an end view of an exemplary embodiment of asuction/infusion catheter 2306 with an occluder 2700 positionedtherethrough. As shown in FIG. 27B, occluder 2700 is shown blockingaperture 2310 to either partially or fully prevent a substance frommoving in or out of blocked aperture 2310. FIG. 27B also shows space2702 whereby a substance may move in and/or out of suction/infusioncatheter 2306, and an optional support wire 2704 positioned within thewall of suction/infusion catheter 2306.

A catheter system 2300, or a portion thereof, according to the presentdisclosure may be used to reinforce a damaged wall of a heart 2400 byaiding in the local delivery of substances to a target site. FIGS. 28Aand 28B show an exemplary embodiment of a suction/infusion catheter 2306used to deliver cells to a target site over the heart 2400. In oneexemplary embodiment described below, magnetic liposomes are deliveredto a damaged left ventricular wall, and fibroblasts are then deliveredto the damaged wall with liposomes to aid in the reinforcement of theventricular wall with a “biologic patch.”

As shown in FIG. 28A, a suction/infusion catheter 2306 is used todeliver, for example, a glue-like substance 2800 to a myocardial infarct2404 (scar site within, for example, a left ventricle) and/or to aborder zone 2406 surrounding the myocardial infarct 2404. Glue-likesubstance may optionally be delivered to remote myocardium 2802 inaddition to being delivered to a myocardial infarct 2404 and/or to aborder zone 2406 surrounding the myocardial infarct 2404. Glue-likesubstance 2800 may comprise, for example, a biologic glue and/or anynumber of vesicles containing magnetic particles, including, but notlimited to, magnetic liposomes. Glue-like substance 2800 may comprisepeptides (not shown) that may assist the seeding of glue-like substance2800 to a myocardial infarct 2404 and/or to a border zone 2406surrounding the myocardial infarct 2404. In one exemplary embodiment,glue-like substance 2800 comprises magnetic liposomes coupled to an RGDpeptide and prepared in accordance to the example provided below.

After glue-like substance 2800 has been delivered to a target site (asshown in FIGS. 28A and 28B), suction/infusion catheter 2306 may be usedto deliver, for example, magnetic cells 2804 to a target site as shownin FIG. 28B. In at least one exemplary embodiment, suction/infusioncatheter 2306 is used to deliver magnetic cells 2804 to a myocardialinfarct 2404 and/or a border zone 2406 having a glue-like substance 2800positioned thereon. In at least one example, glue-like substance 2800comprises magnetic liposomes coupled to an RGD peptide, wherein the RGDpeptide is attracted to the surface of the myocardial infarct 2404and/or the border zone 2406, so that the magnetic liposomes maintaintheir position on the surface of the myocardial infarct 2404 and/or theborder zone 2406 for a period of time. Once the glue-like substance 2800is positioned, magnetic cells 2804 may be delivered by suction/infusioncatheter 2306, which are then attracted to the glue-like substance 2800positioned on the surface of the myocardial infarct 2404 and/or theborder zone 2406. In at least one embodiment, magnetic cells 2804comprise biological cells isolated dermal fibroblasts containingmagnetic particles. It can be appreciated that any number and/or typesof cells suitable for use within the disclosure of the presentapplication are considered to be within the scope of the presentapplication.

In at least one embodiment, magnetic cells 2804 comprise isolated dermalfibroblasts which have been in contact with a glue-like substance 2800prior to delivery to a target site. In at least one example, glue-likesubstance 2800 comprises magnetic liposomes, and when the magneticliposomes are placed in contact with magnetic cells 2804, the magneticcontent of the magnetic liposomes and/or the magnetic liposomesthemselves may be endocytosed by magnetic cells 2804 as described in theexample below. When magnetic cells 2804 are positioned the heart 2400 asdescribed herein, heart 2400 functions as an “in vivo reactor” while thesurface of heart 2400 functions as an as a medium to grow additionalmagnetic cells 2804. As additional magnetic cells 2804 grow within theheart, a tissue may be formed from magnetic cells 2804, providingstructural support to the border zone 2406.

The example provided below represents one method of infarct healing ofthe present disclosure, and is not intended in any way to be indicativeof the only method of performing infarct healing according to thepresent disclosure.

EXAMPLE Preparation of Biologic Patch

In one example, autologous in vitro-cultured fibroblasts containingmagnetic particles are seeded on the affected surface of the heart 2400using a suction/infusion catheter 2306 as described herein. Themagnetized cells may be placed in the infarcted area in order toreinforce the area and to avoid the deleterious effects of wallthickening produced by remodeling after infarction. In one example, themagnetic particles are liposomes formed with a core magnetic vesicle(oxide of Fe 2/3) coated with an amphipathic organic compound(phospholipids and cholesterol), and arginine-glycine-aspartate (RGD)tripeptide coupled with the magnetic liposomes

Cells are cultured and subcultured to be amplified, and then incubatedwith the magnetic particles. These particles are endocytozed by cellsand may then be delivered in the targeted region of magnetized tissues.This method allows the cells to attach to the targeted area and to stayin place while proliferation is carried out. The increased number ofcells on the area would be able to avoid wall thickening and stretching.

Cell Isolation Step: In this example, a skin sample is taken from apatient in aseptic conditions with dermatome. The tissue (skin) samplemust contain epidermis and dermis, avoiding, if possible, the presenceof fat and subcutaneous tissue. The sample is placed in a 50 mL tubecontaining 20 mL Dulbecco's Modified Eagle Media (DMEM) mediumcontaining an antibiotic-antimicotic and 10% irradiated fetal bovineserum. The tube is maintained in a refrigerator until it is processed.

The sample is washed three times with 10 mL phosphate buffer solution(PBS) containing an antibiotic-antimicotic, and then treated for 30 to120 minutes with the enzyme dispase II (Boehringer Mannheim-Roche,catalog no, 165859, 0.5% in Hank's Balanced Salt Solution (HBSS)).Dermis and epidermis are then separated by using forceps.

The dermis is washed three times with HBSS and then treated with theenzyme collagenase I (Sigma, 0.1% in HBSS) for 30-60 minutes, withconstant shaking. When the dermal tissue is disaggregated, it isfiltered with gauze and centrifugated (12400 rpm for 10 minutes). Thesupernatant is discarded and the resulting pellet is resuspended forcell counting. The viability of the isolated cells are estimated by thetrypan blue exclusion method as known in the art.

Cell Culture Step: The isolated dermal fibroblasts are seeded on cellculture dishes or flasks, with an inoculum of 0.7-1.5×104 cells persquare centimeter. The culture medium is DMEM with antibiotic, 10%irradiated fetal bovine serum, and 0.3 μM ascorbic acid. The culturemedium is changed every 2 days. When the fibroblasts reach 70-80%confluence, they are subcultured in order to be amplificated (between1:3 to 1:5).

Cell Subculture Step: For the amplification, the cell culturedishes/flasks are washed two times with PBS (Ca++ and Mg++ free). Thecells are treated with trypsine (Sigma, 0.05%)—EDTA (Sigma, 0.02%), for3-5 minutes. When the cells are detached from culture surface, theenzyme is inhibited with equivalent volume of medium with serum. Thedetached cells are collected, centrifuged, and resuspended in theaforementioned medium. Three to five dishes/flasks are seeded with theobtained cells. This procedure will be repeated until a sufficientnumber of cells are obtained. However, not more than 3rd to 4thsubculture is preferred.

Step of Magnetic Liposomes Preparation: The preparation of magneticliposomes and the coupling to RGD peptide are performed as previouslydescribed herein.

Step of Extraction of Cells Containing Magnetic Liposomes-RGD: Thepreparation of the in vitro cultured fibroblasts containing magneticliposomes coupled to RGD peptide are performed by co-culturing thetrypsinized cells with liposomes-RGD for a period long enough to allowfor the endocytosis of magnetic particles inside the cells. After that,the cells are harvested and are ready for use.

A number of indications and advantages to the aforementioned method ofinfarct healing exist. A method of the present disclosure may assistpatients with severe left ventricular wall impairment due to anterioracute myocardial infarction with or without previous or simultaneousrevascularization procedure (Percutaneous Transluminal CoronaryAngioplasty (PTCA) and/or fibrinolitic). Patients with acute myocardialinfarction cardiogenic shock as a combined procedure with other cardiacsupport devices (an intra aortic balloon pump (IABP), a left ventricularassist device (LVAD), and/or a coronary sinus autoretroperfusion) mayalso benefit from the disclosure of the present application.Furthermore, patients with a low ejection fraction due to an expandedischemic necrotic area with no possibilities to receive coronary arterybypass graft surgery (CABG) or PTCA or failure of PTCA (no reflowphenomenon) may benefit from a procedure as described herein.

Additional benefits to a method of infarct healing of the presentapplication also exist. For example, the procedure may be performedunder local anesthesia, using, for example, an endovascular pericardialsac approach to reach the epicardium target area (acute myocardialinfarct and/or border zone). This procedure may also be combined with apre- or post-PTCA procedure. In addition, and when catheter suctionreaches the acute myocardial infarct and/or border zone area,intermittent or continuous suction begins at the subatmospheric pressuredesired to further facilitate infarct healing.

The devices, systems, and methods of the present disclosure provide forhemodynamic control during a procedure as disclosed herein, utilizing,for example, mean arterial pressure, wedge pressure, central venouspressure, cardiac output, and cardiac index. Evaluation of ventricularfunction with echocardiograms, nuclear magnetic resonance (NMR), ormyocardial echo contrast, for example, may also be performed consistentwith the methods of the present disclosure. In addition to theforegoing, the present disclosure allows for easy insertion and removalof a suction/infusion catheter 2306.

While various embodiments of devices, systems, and methods formyocardial infarct border zone reinforcement have been described inconsiderable detail herein, the embodiments are merely offered by way ofnon-limiting examples of the disclosure described herein. It willtherefore be understood that various changes and modifications may bemade, and equivalents may be substituted for elements thereof, withoutdeparting from the scope of the disclosure. Indeed, this disclosure isnot intended to be exhaustive or to limit the scope of the disclosure.

Further, in describing representative embodiments, the disclosure mayhave presented a method and/or process as a particular sequence ofsteps. However, to the extent that the method or process does not relyon the particular order of steps set forth herein, the method or processshould not be limited to the particular sequence of steps described.Other sequences of steps may be possible. Therefore, the particularorder of the steps disclosed herein should not be construed aslimitations of the present disclosure. In addition, disclosure directedto a method and/or process should not be limited to the performance oftheir steps in the order written. Such sequences may be varied and stillremain within the scope of the present disclosure.

1. A method of myocardial infarct border zone reinforcement, the methodcomprising the steps of: introducing at least one suction/infusioncatheter having a lumen therethrough to a pericardial space surroundinga heart at or near a site of myocardial infarct border zone, the atleast one suction/infusion catheter comprising: one or more aperturesdefined along a portion of the at least one suction/infusion catheter ator near a distal end of the at least one suction/infusion catheter; afirst configuration when the at least one suction/infusion catheter isat least partially extended from a delivery catheter; and a secondconfiguration when the at least one suction/infusion catheter ispositioned within the delivery catheter, the second configurationdifferent from the first configuration; injecting a glue-like substancethrough the lumen of the at least one suction/infusion catheter and outfrom the one or more apertures to deliver the glue-like substance intothe pericardial space at or near the myocardial infarct border zone; andinjecting magnetic cells through the lumen of the at least onesuction/infusion catheter and out from the one or more apertures todeliver the magnetic cells into the pericardial space at or near themyocardial infarct border zone, wherein the magnetic cells are attractedto the glue-like substance, and wherein the magnetic cells providestructural support to the myocardial infarct border zone.
 2. The methodof claim 1, wherein the glue-like substance comprises a biologic glue.3. The method of claim 2, wherein the biologic glue comprises liposomescontaining magnetic particles.
 4. The method of claim 3, wherein theliposomes comprise a peptide attached to an outer surface of theliposomes.
 5. The method of claim 4, wherein the peptide comprises anarginine-glycine-apsartate peptide.
 6. The method of claim 1, whereinthe glue-like substance binds to a myocardial infarct border zone. 7.The method of claim 1, wherein the magnetic cells comprise biologiccells.
 8. The method of claim 7, wherein the biologic cells comprisedermal fibroblasts.
 9. The method of claim 8, wherein the dermalfibroblasts contain magnetic particles.
 10. The method of claim 1,wherein the magnetic cells are attracted to a peptide attached to theglue-like substance.
 11. The method of claim 1, wherein the magneticcells, when positioned within the pericardial space at or near themyocardial infarct border zone, may reproduce to form a tissue, saidtissue providing structural support at the myocardial infarct borderzone.
 12. The method of claim 1, wherein the first configurationcomprises a coiled configuration, and wherein the second configurationcomprises an uncoiled configuration.
 13. The method of claim 1, whereinthe step of introducing the at least one suction/infusion catheter isperformed using a pericardial sac approach.
 14. The method of claim 1,wherein the step of introducing the at least one suction/infusioncatheter is performed by introducing the at least one suction/infusioncatheter into a jugular vein, through a superior vena cava, and into thepericardial space.
 15. The method of claim 1, wherein the step ofintroducing the at least one suction/infusion catheter is performed byintroducing the at least one suction/infusion catheter into a femoralvein, through an inferior vena cava, and into the pericardial space. 16.The method of claim 1, wherein the myocardial infarct border zone is ata left ventricle of the heart, and wherein the step of introducing theat least one suction/infusion catheter comprises the introduction of theat least one suction/infusion catheter into the pericardial space at ornear the left ventricle of the heart.
 17. The method of claim 1, whereinthe at least one suction/infusion catheter further comprises a guidewire positioned at the distal end of the at least one suction/infusioncatheter, wherein the guide wire facilitates introduction of the atleast one suction/infusion catheter in the step of introducing the atleast one suction/infusion catheter.
 18. The method of claim 1, whereinthe step of introducing the at least one suction/infusion catheterfurther comprises extending the at least one suction/infusion catheterfrom the delivery catheter to allow for an increased surface area of atleast one suction/infusion catheter to be positioned at or near themyocardial infarct border zone.
 19. The method of claim 1, furthercomprising the step of introducing an occluder within the lumen of theat least one suction/infusion catheter, wherein the occluder maypartially or completely block one or more apertures of the at least onesuction/infusion catheter.
 20. The method of claim 1, wherein the atleast one suction/infusion catheter further comprises a support wirepositioned along at least part of a length of the at least onesuction/infusion catheter.
 21. The method of claim 20, wherein thesupport wire facilitates the step of introducing at least onesuction/catheter into the pericardial space.
 22. The method of claim 20,further comprising the step of introducing an occluder within the lumenof the at least one suction/infusion catheter, wherein the step ofintroducing an occluder is facilitated by the support wire.
 23. A methodof myocardial infarct border zone reinforcement, the method comprisingthe steps of: introducing at least one suction/infusion catheter havinga lumen therethrough to a pericardial space surrounding a heart at ornear a site of myocardial infarct border zone, the at least onesuction/infusion catheter comprising: one or more apertures definedalong a portion of the at least one suction/infusion catheter at or neara distal end of the at least one suction/infusion catheter; a firstconfiguration when the at least one suction/infusion catheter is atleast partially extended from a delivery catheter; and a secondconfiguration when the at least one suction/infusion catheter ispositioned within the delivery catheter, the second configurationdifferent from the first configuration; injecting a glue-like substancecomprising a biologic glue through the lumen of the at least onesuction/infusion catheter and out from the one or more apertures todeliver the glue-like substance into the pericardial space at or nearthe myocardial infarct border zone; and injecting magnetic cells throughthe lumen of the at least one suction/infusion catheter and out from theone or more apertures to deliver the magnetic cells into the pericardialspace at or near the myocardial infarct border zone, wherein themagnetic cells are attracted to the glue-like substance, and wherein themagnetic cells provide structural support to the myocardial infarctborder zone.
 24. The method of claim 23, wherein the biologic gluecomprises liposomes containing magnetic particles.
 25. The method ofclaim 24, wherein the liposomes comprise a peptide attached to an outersurface of the liposomes.
 26. The method of claim 23, wherein themagnetic cells comprise biologic cells.
 27. The method of claim 26,wherein the biologic cells comprise dermal fibroblasts.
 28. The methodof claim 23, wherein the myocardial infarct border zone is at a leftventricle of the heart, and wherein the step of introducing the at leastone suction/infusion catheter comprises the introduction of the at leastone suction/infusion catheter into the pericardial space at or near theleft ventricle of the heart.
 29. The method of claim 23, wherein thestep of introducing the at least one suction/infusion catheter furthercomprises extending the at least one suction/infusion catheter from thedelivery catheter to allow for an increased surface area of at least onesuction/infusion catheter to be positioned at or near the myocardialinfarct border zone.
 30. A method of myocardial infarct border zonereinforcement, the method comprising the steps of: introducing at leastone suction/infusion catheter having a lumen therethrough to apericardial space surrounding a heart at or near a site of myocardialinfarct border zone, the at least one suction/infusion cathetercomprising: one or more apertures defined along a portion of the atleast one suction/infusion catheter at or near a distal end of the atleast one suction/infusion catheter; a coiled configuration when the atleast one suction/infusion catheter is at least partially extended froma delivery catheter; and an uncoiled configuration when the at least onesuction/infusion catheter is positioned within the delivery catheter,the uncoiled configuration different from the coiled configuration;injecting a glue-like substance through the lumen of the at least onesuction/infusion catheter and out from the one or more apertures todeliver the glue-like substance into the pericardial space at or nearthe myocardial infarct border zone; and injecting magnetic cells throughthe lumen of the at least one suction/infusion catheter and out from theone or more apertures to deliver the magnetic cells into the pericardialspace at or near the myocardial infarct border zone, wherein themagnetic cells are attracted to the glue-like substance, and wherein themagnetic cells provide structural support to the myocardial infarctborder zone.
 31. The method of claim 30, wherein the biologic gluecomprises liposomes containing magnetic particles.
 32. The method ofclaim 31, wherein the liposomes comprise a peptide attached to an outersurface of the liposomes.
 33. The method of claim 30, wherein themagnetic cells comprise biologic cells.
 34. The method of claim 33,wherein the biologic cells comprise dermal fibroblasts.
 35. The methodof claim 30, wherein the myocardial infarct border zone is at a leftventricle of the heart, and wherein the step of introducing the at leastone suction/infusion catheter comprises the introduction of the at leastone suction/infusion catheter into the pericardial space at or near theleft ventricle of the heart.
 36. The method of claim 30, wherein thestep of introducing the at least one suction/infusion catheter furthercomprises extending the at least one suction/infusion catheter from thedelivery catheter to allow for an increased surface area of at least onesuction/infusion catheter to be positioned at or near the myocardialinfarct border zone.
 37. The method of claim 30, wherein the step ofintroducing the at least one suction/infusion catheter is performed byintroducing the at least one suction/infusion catheter into a jugularvein, through a superior vena cava, and into the pericardial space.